Exploring antiviral effect and mechanism of Jinye Baidu granules（JYBD）against influenza A virus through network pharmacology and in vitro and invivo experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinye Baidu granules (JYBD) have been used to treat acute respiratory tract infections and demonstrated clinical efficacy for the treatment of emerging or epidemic respiratory viruses such as SARS-CoV-2 and influenza virus. AIM OF THE STUDY: This study is to investigate the antiviral effect of JYBD against influenza A viruses (IAV) in vitro and in vivo and elucidate its underlying mechanism. MATERIALS AND METHODS: Ultra-high-performance liquid chromatography connected with Orbitrap mass spectrometer (UHPLC-Orbitrap MS) was employed to describe the chemical profile of JYBD. The potential pathways and targets involved in JYBD against IAV infection were predicted by network pharmacology. The efficacy and mechanism of JYBD were validated through both in vivo and in vitro experiments. Moreover, combination therapy with JYBD and the classic anti-influenza drugs was also investigated. RESULTS: A total of 126 compounds were identified by UHPLC-Orbitrap MS, of which 9 compounds were unambiguously confirmed with reference standards. JYBD could significantly inhibit the replication of multiple strains of IAV, especially oseltamivir-resistant strains. The results of qRT-PCR and WB demonstrated that JYBD could inhibit the excessive induction of pro-inflammatory cytokines induced by IAV infection and regulate inflammatory response through inhibiting JAK/STAT, NF-κB and MAPK pathways. Moreover, both JYBD monotherapy or in combination with oseltamivir could alleviate IAV-induced severe lung injury in mice. CONCLUSIONS: JYBD could inhibit IAV replication and mitigate virus-induced excessive inflammatory response. Combinations of JYBD and neuraminidase inhibitors conferred synergistic suppression of IAV both in vitro and in vivo. It might provide a scientific basis for clinical applications of JYBD against influenza virus infected diseases.

Unveiling the therapeutic potential and mechanisms of stanniocalcin-1 in retinal degeneration.

Retinal degeneration (RD) is a group of ocular diseases characterized by progressive photoreceptor apoptosis and visual impairment. Mitochondrial malfunction, excessive oxidative stress, and chronic activation of neuroglia collectively contribute to the development of RD. Currently, there is a lack of efficacious therapeutic interventions for RD. Stanniocalcin-1 (STC-1) is a promising candidate molecule to decelerate photoreceptor cell death. STC-1 is a secreted calcium/phosphorus regulatory protein that exerts diverse protective effects. Accumulating evidence suggests that STC-1 protects retinal cells from ischemic injury, oxidative stress, and excessive apoptosis through enhancing the expression of uncoupling protein-2 (UCP-2). Furthermore, STC-1 exerts its antiinflammatory effects by inhibiting the activation of microglia and macrophages, as well as the synthesis and secretion of proinflammatory cytokines, such as TNF-α, IL-1, and IL-6. By employing these mechanisms, STC-1 effectively shields the retinal photoreceptors and optic nerve, thereby slowing down the progression of RD. We summarize the STC-1-mediated therapeutic effects on the degenerating retina, with a particular focus on its underlying mechanisms. These findings highlight that STC-1 may act as a versatile molecule to treat degenerative retinopathy. Further research on STC-1 is imperative to establish optimal protocols for its clinical use.

Bacillus licheniformis suppresses Clostridium perfringens infection via modulating inflammatory response, antioxidant status, inflammasome activation and microbial homeostasis in broilers.

Pathogenic bacteria infection, especially Clostridium perfringens (C. perfringens), markedly threatened the health of animals, and further caused huge economic loss. In this study, Bacillus licheniformis HJ0135 (BL) was used. Oxford cup bacteriostatic test and inhibitory rate test were conducted to evaluate the antibacterial ability of BL. Results showed the strongest inhibitory role of BL on C. perfringens (P < 0.05). Afterwards, 540 one-day-old yellow-feather broilers (32.7 ± 0.2 g) were randomly allocated into 3 groups, including CON group (basal diet), CP group (basal diet + 1 × 109 CFU C. perfringens in gavage), and BL + CP group (basal diet containing 7.5 × 106 CFU/g BL + 1 × 109 CFU C. perfringens in gavage). At d 70, broilers in the CP and BL + CP groups were treated with C. perfringens by continuously oral administration for 5 d. The experiment lasted for 75 d. The serum, immune organs, jejunal mucosa, and cecal contents were collected for analysis. In vivo experiment showed that BL supplementation markedly improved (P < 0.05) BW, ADG, thymus index, serum immunoglobins and antioxidases, reduced feed conversion ratio (FCR) and serum pro-inflammatory cytokines of C. perfringens-infected broilers. Furthermore, the increased jejunal injury and levels of pro-inflammatory cytokines, decreased gene expressions of tight junction proteins in the jejunal mucosa were significantly alleviated (P < 0.05) by BL. More importantly, the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome was inhibited (P < 0.05) by BL to further attenuate jejunal damage. Besides, BL supplementation markedly increased (P < 0.05) the cecal isobutyric acid and isovaleric acid. Microbial analysis showed that BL changed the composition and relative abundances of microbiota in the cecal contents (P < 0.05), especially the short chain fatty acids (SCFAs)-producing bacteria including Eubacterium_coprostanoligenes_group, Megamonas, Faecalibacterium, and Lactobacillus, which further protected against C. perfringens-induced jejunal inflammation in broilers. Our study laid a theoretical basis for the application of probiotics in lessening C. perfringens-related diseases in poultry farming.

Interplay between Pro-inflammatory Mediators and Oxidative Stressinvolved Recurrent Chronic Heart Failure in Elderly Patients with Coronary Stents.

INTRODUCTION: Inflammation and oxidative stress are related to congestive heart failure in patients with coronary heart disease. OBJECTIVE: Chronic congestive heart failure is a serious stage of coronary artery disease and is mainly a disease of elderly people over the age of 65. Elderly heart failure patients are characterized by myocardial ischemia, and post-ischemic myocardial dysfunction. Oxidative Stress, inflammation, and immune response play important roles in the development of heart failure. We tried to examine the mutual triggering of oxidative stress (malondialdehyde), inflammatory cytokines (tumor necrosis factor-α and soluble tumor necrosis factor receptor-1/2), immune response (toll-like receptors 2,3,4), and high sensitivity C-reactive protein expression in elderly patients with recurrent congestive heart failure after coronary stenting and investigated the effect of interplay of these changes on onset and progression of recurrent congestive heart failure in elderly patients underwent coronary stent implantation. METHODS: A total of 726 patients were enrolled in this study. We determined the levels of malondialdehyde (MDA), high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF- α), soluble tumor necrosis factor receptor-1 and 2 (sTNFR-1/2) and toll-like receptor 2,3,4 (TLR2/3/4) in elderly patients with recurrent congestive heart failure after coronary artery stent implantation. RESULTS: Levels of MDA, hs-CRP, TNF-α, sTNFR-1, sTNFR-2, TLR2, TLR3 and TLR4 were remarkably increased (p<0.01) in elderly patients with recurrent congestive heart failure after coronary artery stenting. The results indicated that these markers were closely correlated to each other and showed that these markers were associated with increased New York Heart Association functional classification and low left ventricular ejection fractions. Further analysis confirmed that the independent clinical risk factors for recurrent congestive heart failure were MDA, hs-CRP, TNF-α, sTNFR-1, sTNFR-2, TLR2, TLR3 and TLR4. The interplay of oxidative stress, inflammatory cytokines and toll-like receptors, and hs-CRP expression levels was an important factor involved in recurrent congestive heart failure of elderly patients after coronary stenting. CONCLUSION: High levels of MDA, hs-CRP, TNF-α, sTNFR-1, sTNFR-2, TLR2, TLR3 and TLR4 had an important implication for recurrent heart failure with increased New York Heart Association functional classification and low left ventricular ejection fractions. These eight factors amplified each other's positive effects and this interaction may be a key element of their roles in recurrent heart failure. The eight risk factors were inter-dependent and occurred simultaneously, and exerted detrimental effects forming a vicious circle. MDA may trigger the over-expressions of pro-inflammatory risk factors (hs-CRP, TNF-α, sTNFR-1, sTNFR-2) through the activation of TLRs as risk factors (TLR2, TLR3 and TLR4) contributing to the dysfunction of myocardial mitochondria, cardiomyocyte hypertrophy, maladaptive myocardial remodeling, myocardial interstitial fibrosis, cardiac systolic decrease and recurrent heart failure. These eight risk factors were the basis of the mechanisms of recurrent heart failure. Therefore, the mutual triggering of oxidative stress, inflammatory and toll-like receptor signaling pathways, and hs-CRP expression could play key roles in the development of recurrent congestive heart failure in elderly patients after coronary stenting.

TNFα and IL-8 vitreous concentrations variations with two antidiabetic therapies in patients with proliferative diabetic retinopathy: an observational study.

BACKGROUND: Antidiabetic therapies are effective, but could indirectly modify the inflammatory response in the ocular microenvironment; therefore, a study was developed to evaluate the inflammatory cytokine profile in the vitreous humor of diabetic patients with retinopathy under treatment with antidiabetic drugs. METHODS: Observational, comparative, retrospective, cross-sectional study. Interleukins 1ß, 6, 8, 10, and tumor necrosis factor-alpha (TNFα) were evaluated in the vitreous humor obtained from patients with type 2 diabetes mellitus, proliferative diabetic retinopathy, and concomitant retinal detachment or vitreous hemorrhage, and who were already on antidiabetic treatment with insulin or metformin + glibenclamide. The quantification analysis of each cytokine was performed by the cytometric bead array (CBA) technique; medians and interquartile ranges were obtained, and the results were compared between groups using the Mann-Whitney U test, where a p-value < 0.05 was considered significant. RESULTS: Thirty-eight samples; quantification of TNFα concentrations was higher in the group of patients administered insulin, while interleukin-8 was lower; in the metformin + glibenclamide combination therapy group, it occurred inversely. In the stratified analysis, the highest concentrations of interleukin-8 and TNFα occurred in patients with vitreous hemorrhage; however, the only statistical difference existed in patients with retinal detachment, whose TNFα concentration in the combined therapy group was the lowest value found (53.50 (33.03-86.66), p = 0.03). Interleukins 1ß, 6, and 10 were not detected. CONCLUSION: Interleukin-8 and TNFα concentrations are opposite between treatment groups; this change is more accentuated in patients with proliferative diabetic retinopathy and vitreous hemorrhage, where the highest concentrations of both cytokines are found, although only TNFα have statistical difference.

The systemic inflammatory response index is associated with chronic kidney disease in patients with hypertension: data from the national health and nutrition examination study 1999-2018.

BACKGROUND: Studies have shown that in hypertensive patients, chronic kidney disease (CKD) is associated with a poor prognosis. Inflammation is a highly important factor in the progression of CKD. Detecting systemic inflammation and intervening promptly in patients with hypertension may help reduce the risk of CKD. The systemic inflammatory response index (SIRI) is a tool used to measure the systemic inflammatory response, but its relationship with CKD in patients with hypertension remains uncertain. METHODS: We utilized data from the National Health and Nutrition Examination Survey (NHANES), which was conducted between 1999 and 2018. The analysis included a total of 20,243 participants, categorized into three groups based on SIRI tertiles. Logistic regression analysis and restricted cubic spline analysis were used to examine the relationship between the SIRI and CKD. RESULTS: In patients with hypertension, there was a notable relationship between the SIRI and the odds of developing CKD. After full adjustment, there was a 31% greater likelihood of developing CKD associated with each incremental increase of 1 unit in the SIRI (OR: 1.31, 95% CI: 1.24-1.39, p < 0.001). The groups with greater SIRI values exhibited greater odds of developing CKD than did the T1 group (T2: OR: 1.20, 95% CI: 1.04-1.38, p = 0.015; T3: OR: 1.69, 95% CI: 1.47-1.94, p < 0.001). CONCLUSION: A high SIRI is associated with an increased risk of CKD in hypertensive patients. The greater the SIRI is, the greater the risk of CKD in hypertensive patients.

Remifentanil-induced inflammation in microglial cells: Activation of the PAK4-mediated NF-κB/NLRP3 pathway and onset of hyperalgesia.

BACKGROUND: The perioperative use of remifentanil is associated with postoperative hyperalgesia, which can impair recovery and extend hospitalization. Recent studies have revealed that microglia-mediated activation of the NLRP3 inflammasome plays a critical role in opioid-induced hyperalgesia, with NF-κB acting as a pivotal activation point for NLRP3. Despite these findings, the specific molecular mechanisms underlying remifentanil-induced postoperative hyperalgesia remain unclear. This study aims to develop a model of remifentanil-induced hyperalgesia and investigate the molecular mechanisms, focusing on the NF-κB/NLRP3 pathway, using both in vitro and in vivo approaches. METHOD: We established a remifentanil-induced hyperalgesia model and performed proteomic analysis to identify differential protein expression in the spinal cord tissue of rats. NLRP3 or PAK4 antagonists were administered intrathecally in vivo, and mechanical pain thresholds in the hind paws were measured using Von Frey testing. In vitro, we applied NLRP3 or PAK4 inhibitors or used lentivirus infection to silence PAK4, NF-κB, and NLRP3 genes. Protein expression was assessed through immunohistochemistry, immunofluorescence, and Western blotting. Additionally, ELISA was performed to measure IL-1ß and IL-18 levels, and RT-qPCR was conducted to evaluate the transcription of target genes. RESULTS: Proteomic analysis revealed that remifentanil upregulates PAK4 protein in spinal cord tissue two hours after the surgery. In addition, remifentanil induces morphological changes in the spinal cord dorsal horn, characterized by increased expression of PAK4, p-p65, NLRP3 and Iba-1 proteins, which in turn leads to elevated IL-1ß and IL-18 levels and an inflammatory response. Intrathecal injection of NLRP3 or PAK4 inhibitors mitigates remifentanil-induced hyperalgesia and associated changes. In vitro, downregulation of PAK4 inhibits the increase in PAK4, p-p65, NLRP3 and Caspase-1 induced by LPS. Conversely, the downregulation of NLRP3 does not impact the levels of PAK4 and p-p65 proteins, aligning with the in vivo results and suggesting that PAK4 acts as an upstream signaling molecule of NLRP3. CONCLUSION: Remifentanil can increase PAK4 expression in spinal cord dorsal horn cells by activating the NF-κB/NLRP3 pathway and mediating microglial activation, thereby contributing to postoperative hyperalgesia.

An exploratory study of cervical disc degeneration model and mechanism of acupuncture therapy in rabbits.

Acupuncture is an important therapy method in traditional Chinese medicine for treating intervertebral disc degeneration (IVDD), offering a wide range of applications. It is based on the theory of Chinese veterinary medicine and combines the stage of the disease course and individual differences for syndrome differentiation and treatment. However, there are few studies on the acupuncture treatment of cervical disc degeneration (CDD) in rabbits. Treatment based on syndrome differentiation is the basic principle of Chinese veterinary treatment. The selection of acupoints for external treatment should be based on individual etiology and pathogenesis. Nevertheless, most current studies do not follow this guideline. In this study, we established the CDD model and explored the mechanism of acupuncture treatment in alleviating CDD in rabbits by selecting a group of main acupoints including cervical Jiaji, Fengchi, Tianzhu, Naohu, Dazhui, and Houxi acupoints, combined with Western medicine's understanding of the pathogenesis of cervical spondylosis, from the anti-inflammatory, analgesic, and tissue-repairing perspectives. Magnetic resonance imaging (MRI) confirmed the successful establishment of the rabbit CDD model. Acupuncture stimulation reduced the increase of average and maximum neck temperature due to CDD in rabbits. The acupuncture treatment relieved the spinal disc damage in the neck of the rabbit, which also decreased the expression level of pro-apoptotic factor Bax and increased the expression level of anti-apoptotic factor Bcl-2. In addition, it can alleviate the abnormal apoptosis of rabbit intervertebral disc, decrease the expression level of inflammatory factors such as TNF-α, IL-1ß, IL-2, and PGE2α, and alleviate the intense inflammation and pain response caused by CDD in rabbits. In conclusion, Acupuncture treatment can slow down the CDD of rabbits by regulating the inflammatory response and abnormal apoptosis of intervertebral disc tissue.

Tropomodulin1 exacerbates inflammatory response in macrophages by negatively regulating LPS-induced TLR4 endocytosis.

The excessive inflammation caused by the prolonged activation of Toll-like receptor 4 (TLR4) and its downstream signaling pathways leads to sepsis. CD14-mediated endocytosis of TLR4 is the key step to control the amount of TLR4 on cell membrane and the activity of downstream pathways. The actin cytoskeleton is necessary for receptor-mediated endocytosis, but its role in TLR4 endocytosis remains elusive. Here we show that Tropomodulin 1 (Tmod1), an actin capping protein, inhibited lipopolysaccharide (LPS)-induced TLR4 endocytosis and intracellular trafficking in macrophages. Thus it resulted in increased surface TLR4 and the upregulation of myeloid differentiation factor 88 (MyD88)-dependent pathway and the downregulation of TIR domain-containing adaptor-inducing interferon-ß (TRIF)-dependent pathway, leading to the enhanced secretion of inflammatory cytokines, such as TNF-α and IL-6, and the reduced secretion of cytokines, such as IFN-ß. Macrophages deficient with Tmod1 relieved the inflammatory response in LPS-induced acute lung injury mouse model. Mechanistically, Tmod1 negatively regulated LPS-induced TLR4 endocytosis and inflammatory response through modulating the activity of CD14/Syk/PLCγ2/IP3/Ca2+ signaling pathway, the reorganization of actin cytoskeleton, and the membrane tension. Therefore, Tmod1 is a key regulator of inflammatory response and immune functions in macrophages and may be a potential target for the treatment of excessive inflammation and sepsis.

Multiple site inflammation and acute kidney injury in crush syndrome.

Crush syndrome, which frequently occurs in earthquake disasters, often leads to rhabdomyolysis induced acute kidney injury (RIAKI). Recent findings indicate that systemic inflammatory response syndrome (SIRS) exacerbates muscle collapse, contributing to RIAKI. The purpose of this study is to investigate the involvement of multiple site inflammation, including intraperitoneal, in crush syndrome. In a mouse model of RIAKI, elevated levels of inflammatory mediators such as TNFα, IL-6, myoglobin, and dsDNA were observed in serum and the peritoneal cavity, peaking earlier in the intraperitoneal cavity than in serum or urine. Our previously developed novel peptide inhibiting leukocyte extracellular traps was administered intraperitoneally and blocked all of these mediators in the intraperitoneal cavity and serum, ameliorating muscle damage and consequent RIAKI. Although further studies are needed to determine whether intraperitoneal inflammation associated with muscle collapse can lead to systemic inflammation, resulting in more severe and prolonged muscle damage and renal injury, early suppression of multiple site inflammation, including intraperitoneal, might be an effective therapeutic target.

A Novel Porphyromonas gingivalis Infection-Related Inflammatory Response-Related Genes Signature Predicts the Prognosis of Esophageal Squamous Cell Carcinoma.

Background: Our previous research showed that Porphyromonas gingivalis (P. gingivalis) infection can activate the inflammatory signaling pathway and promotes the malignancy development of esophageal squamous cell carcinoma (ESCC). However, the prognostic significance of inflammatory response-related genes (IRRGs) in P. gingivalis-infected ESCC requires further elucidation. Hence, our study constructed a prognostic signature based on P. gingivalis and IRRGs to forecast the survival of patients with ESCC, which may provide insight into new treatment options for ESCC patients. Methods: Differentially expressed genes (DEGs) were identified in P.gingivalis-infected and P.gingivalis-uninfected ESCC cell by RNA sequencing. A risk model was constructed and validated using the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database by using univariate Cox regression analysis, LASSO, and the multivariate Cox regression analysis. Kaplan-Meier analysis was carried out to compare the overall survival (OS) between high-risk and low-risk groups. Single-sample gene set enrichment analysis was used to analyze the immune cell infiltration. The Genomics of Drug Sensitivity in Cancer database was used to predict drug sensitivity. Results: There were 365 DEGs between the P.gingivalis-infected and P.gingivalis-uninfected groups. Four genes including DKK1, ESRRB, EREG, and RELN were identified to construct the prognostic risk model (P = .012, C-index = 0.73). In both the training and validation sets, patients had a considerably shorter OS in the high-risk group than those in the low-risk group (P < .05). A nomogram was established using the risk score, gender, and N stage which could effectively forecast the prognosis of patients (P = .016, C-index = 0.66). The high-risk group displayed lower immune infiltrating cells, such as activated dendritic cells, type 2 T helper cells, and neutrophils (P < .05). A total of 41 drugs, including dactinomycin, luminespib, and sepantronium bromide, had a significant difference in IC50 between the 2 subgroups. Conclusion: We demonstrated the potential of a novel signature constructed from 4 P. gingivalis-related IRRGs for prognostic prediction in ESCC patients.

The role of cytokines in the pathogenesis of SAPHO syndrome.

SAPHO syndrome is a complex inflammatory disorder affecting the skin and bones, characterized by osteomyelitis, acne, and pustulosis. Cytokines play a pivotal role in the pathogenesis of SAPHO syndrome, especially in inflammatory responses and immune regulation. This article reviews the cytokines involved in the pathogenesis of SAPHO syndrome, such as tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), IL-6, IL-10, and transforming growth factor-ß (TGF-ß), and discusses their potential as intervention points for treatment. These findings elucidate the intricate immune regulatory network of SAPHO syndrome and provide a theoretical foundation for the development of new targeted therapeutic strategies.

Palmatine ameliorates N-methyl-N'-nitrosoguanidine-induced chronic atrophic gastritis through the STAT1/CXCL10 axis.

Chronic atrophic gastritis (CAG) is a prevalent preneoplastic condition of the stomach. Palmatine (PAL), an isoquinoline alkaloid isolated from Rhizoma Coptidis (RC), has significant anti-inflammatory properties and is often used to treat gastrointestinal disorders. However, the mechanism of PAL on CAG remains unclear. In this study, N-methyl-N'-nitrosoguanidine (MNNG) was used to induce CAG inflammatory disease models in vivo and in vitro. The efficacy of five alkaloids in RC and the dose-dependent effects of the most effective PAL in CAG mice were evaluated in two animal experiments. RNA-seq and western blot revealed that PAL significantly improved IL-17, TNF, and NF-kappa B inflammation-related signaling pathways. Further hub gene prediction and experimental validation revealed that PAL modulated the STAT1/CXCL10 axis, thereby exerting attenuation of CAG through the regulation of IL-17, TNF-α, and p-p65 expression. In conclusion, PAL was proposed to mitigate MNNG-induced CAG, potentially through the inhibition of oxidative stress and inflammatory responses via the STAT1/CXCL10 axis. This approach is an effective complement to the use of PAL in the treatment of CAG.

Calcium enrichment activity initiates extracellular calcium influx-dependent inflammatory response of biologically-derived hydroxyapatite.

Biologically-derived hydroxyapatite is a widely used biomaterial in various clinical applications including bone augmentation. However, the osteogenic application of biological hydroxyapatite is limited by inflammatory responses, and the underlying mechanism remains unknown. The current study aimed to elucidate the molecular mechanisms underlying the inflammatory response to biological hydroxyapatite. Porcine-derived hydroxyapatite (PHA) with two sintering temperatures (800 and 1600 °C), PHA800 and PHA1600, respectively, were prepared. A PHA/macrophage co-culture model was established. Transcriptome, polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA) analyses were used to determine the inflammatory effects and the main pathways activated by PHA800 and PHA1600. Intracellular calcium level, PHA-induced calcium enrichment, and related biological effects were used to determine the molecular mechanism at the PHA-cell interface. PHA800 significantly upregulated a TLR4 mediated inflammatory pathway in a calcium influx-dependent manner, and the calcium enrichment activity on the surface of PHA800 promoted calcium influx. In contrast, the calcium enrichment activity on the surfaces of the PHA1600 and PHA800 pretreated groups was attenuated, resulting in decreased calcium influx and mild inflammatory effects. Our results provide a fundamental basis for the development of novel bone substitutes that elicit low levels of inflammation response.

MRI changes in cryptococcal meningoencephalitis exacerbated by antifungal treatment due to post-infectious inflammatory syndrome: A case report.

Cryptococcal meningitis is one of the most common fungal meningitis in adults and causes disabling morbidity and mortality worldwide. The occurrence of postinfectious inflammatory response syndrome during cryptococcal meningitis treatment presents a diagnostic challenge. This time course seems paradoxical because patients show worsening symptoms and imaging findings. However, laboratory data improve with antifungal treatments. Herein, we present a case of an older woman diagnosed with cryptococcal meningitis who later developed postinfectious inflammatory response syndrome. Despite the initial antifungal treatment and improvements in cerebrospinal fluid analysis results, the patient's neurological condition deteriorated; imaging findings worsened. Magnetic resonance imaging at the time of postinfectious inflammatory response syndrome showed more prominent meningeal enhancement and brain edema, consistent with postinfectious inflammatory response syndrome, combined with negative repeat cerebrospinal fluid cultures for cryptococcal species. This case highlights the importance of considering postinfectious inflammatory response syndrome when patients with cryptococcal meningitis show clinical worsening during treatment. Prompt corticosteroid therapy significantly improves patient outcomes. Radiologists and clinicians should be aware of postinfectious inflammatory response syndrome to provide appropriate therapeutic options and improve prognosis in patients with cryptococcal meningitis.

Geniposide ameliorates diabetic nephropathy in type 2 diabetic mice by targeting AGEs-RAGE-dependent inflammatory pathway.

BACKGROUND: Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus and the primary cause of morbidity and mortality in end-stage renal disease. The receptor for advanced glycation end products (RAGE) plays a crucial role in mediating AGE-triggered inflammation, which has been implicated in DN pathogenesis. While geniposide, a natural compound, has demonstrated anti-inflammatory and hypoglycemic properties, its potential to mitigate AGE-induced renal inflammation and consequently impede DN progression remains unexplored. PURPOSE: The objective of this study was to ascertain whether geniposide is a novel natural AGEs-RAGE blocker and to investigate its protective effect on renal DN in type 2 diabetic mice. METHODS: Binding affinity between geniposide and RAGE was assessed using MicroScale Thermophoresis (MST), molecular docking, and co-immunoprecipitation. RAGE was then subjected to knockdown and overexpression in cellular experiments to evaluate geniposide's effects on AGE-induced inflammatory responses and the RAGE pathway. Finally, db/db mice were employed to validate the renoprotective effects of geniposide in DN. RESULTS: Geniposide exhibited higher binding affinity to RAGE's V domain than AGEs, competitively inhibiting AGEs-RAGE interaction through hydrogen bonding. It suppressed RAGE expression and RAGE-dependent inflammatory responses to AGEs, comparable to RAGE siRNA effects. In RAGE-overexpressing cells, geniposide further inhibited AGEs-induced ERK1/2 and NFκB P65 activation, reducing inflammatory marker levels. Long-term oral administration of geniposide to db/db mice improved plasma creatinine, urea, and proteinuria levels, ameliorated pathological changes, and downregulated inflammatory factors such as TNF-α and IL-1ß. Moreover, it dose-dependently attenuated enhanced renal expression of RAGE, phosphorylated ERK1/2, IκB-α, and NF-κB P65. CONCLUSION: Geniposide effectively attenuates AGEs-induced RAGE activation by directly blocking AGEs-RAGE signal transduction, thereby mitigating inflammatory responses. These findings suggest that geniposide has potential as a high-affinity RAGE antagonist, potentially playing a crucial role in the treatment of DN.

A Nontoxic and Biocompatible Method for Augmenting Mechanical Strength of Acellular Matrix by Silk Fibroin Impregnation.

Biological scaffolds are plagued by poor biomechanical properties and untimely degradation. These limitations have yet to be addressed without compromising their biocompatibility. It is desirable to avoid inflammation and have degradation with concomitant host collagen deposition or even site-appropriate in situ regeneration for the successful outcome of an implanted biological scaffold. This work aims to achieve this by utilizing a biocompatible method to modify acellular scaffolds by impregnating alkaline-catalyzed citric acid (CA) cross-linking between the extracellular matrix proteins and silk fibroin (SF)/SF-gelatin (SFG) blends. Combinatorial detergent decellularization was employed to prepare a decellularized porcine liver scaffold (DPL). After proving the decellularization efficiency, the scaffold underwent modification by vacuum impregnation with CA containing SF (SF100DPL) and SFG blends (SFG5050DPL and SFG3070DPL) following pre-cross-linking, drying, and post-cross-linking. The subsequent strength augmentation was demonstrated by significant improvement in tensile strength from 2.4 ± 0.4 MPa (DPL) to, 3.8 ± 0.7 MPa (SF100DPL), 3.4 ± 0.7 MPa (SFG5050DPL), and 3.5 ± 0.2 MPa (SFG3070DPL); Young's modulus from 8.7 ± 1.8 MPa (DPL) to 20 ± 1.9 MPa (SF100DPL), 13.3 ± 2.6 MPa (SFG5050DPL), and 16 ± 1.2 MPa (SFG3070DPL); and suture retention strength from 0.9 ± 0.08 MPa (DPL) to 2.3 ± 0.2 MPa (SF100DPL), 2.8 ± 1.2 MPa (SFG5050DPL), and 2.6 ± 0.9 MPa (SFG3070DPL). The degradation resistance of the modified scaffolds was also markedly improved. Being cytocompatible, its ability to incite tolerable inflammatory and immune responses was confirmed by rat subcutaneous implantation for 14, 30, and 90 days, in terms of inflammatory cell infiltration, neoangiogenesis, and in vitro cytokine release to assess B-cell and T-cell activation. Such ECM composite scaffolds with appropriate strength and biocompatibility offer great promise in soft tissue repair applications such as skin grafting.

Moxibustion with seed-size moxa cones alleviates colonic injury in mice with ulcerative colitis by regulating TLR4/MyD88/NF-κB signaling pathway. / 麦粒灸调控TLR4/MyD88/NF-κBä¿¡å·é€šè·¯å‡è½»æºƒç–¡æ€§ç»“è‚ ç‚Žå°é¼ ç»“è‚ æŸä¼¤çš„æœºåˆ¶ç ”ç©¶.

OBJECTIVES: To observe the effect of moxibustion with seed-size moxa cones on the Toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear transcription factor-κB(NF-κB) signaling pathway in mice with ulcerative colitis(UC), so as to explore the therapeutic mechanism of moxibustion with seed-size moxa cones on colonic injury in UC. METHODS: Forty male C57BL/6 mice were randomly divided into blank group, model group, moxibustion group, and western medicine group, with 10 mice in each group. The UC mouse model was established by 3% DSS solution by free drinking for 7 consecutive days. Mice in the moxibustion group were treated with seed-size moxa cones at "Zhongwan"(CV12), "Tianshu"(ST25) and "Shangjuxu"(ST37), 3 moxa cones per point, with each cone applied for approximately 30 s, while mice in the western medicine group were orally administered with 300 mg/kg mesalazine solution, which were both conducted once a day for 7 consecutive days. The general condition of mice was observed every 2 days, and the disease activity index (DAI) score was calculated. HE staining was used to observe the morphology of colonic tissue in mice. ELISA was used to detect the serum interleukin(IL)-1ß, tumor necrosis factor(TNF)-α, IL-6, and IL-8 contents. Immunohistochemistry was used to detect the positive expression of TLR4 and MyD88 in colonic tissue of mice. Real-time fluorescence quantitative PCR was used to detect the expression levels of TLR4, MyD88, and NF-κB p65 mRNAs in colonic tissue. RESULTS: Compared with the blank group, varying degrees of soft or watery stools were observed, colon length and body weight were decreased(P<0.01) in mice of the model group, while DAI score, colon weight index, mucosal damage score, colonic pathological score, serum IL-1ß, TNF-α, IL-6, and IL-8 contents, positive expressions of TLR4 and MyD88, and TLR4, MyD88, and NF-κB p65 mRNA expressions in colonic tissue were increased(P<0.01). Compared with the model group, improved fecal characteristics were observed, colon length and body weight were increased(P<0.01) in mice of the moxibustion group and western medicine group, while DAI scores, colon weight indexes, mucosal damage scores, colonic pathological score, serum contents of IL-1ß, TNF-α, IL-6, and IL-8, positive expressions of TLR4 and MyD88, and TLR4, MyD88, and NF-κB p65 mRNA expressions in colonic tissue were decreased(P<0.01, P<0.05). There was no significant difference in the above indicators between the moxibustion group and the western medicine group. CONCLUSIONS: Moxibustion with seed-size moxa cones may alleviate colonic injury in UC mice by regulating the TLR4/MyD88/NF-κB signaling pathway and reducing the release of inflammatory factors.

Pathogenesis and potential diagnostic biomarkers of atrial fibrillation in Chinese population: a study based on bioinfor-matics. / åŸºäºŽç”Ÿç‰©ä¿¡æ¯å­¦æŽ¢è®¨ä¸­å›½äººç¾¤å‘ç”Ÿå¿ƒæˆ¿é¢¤åŠ¨çš„æœºåˆ¶åŠæ½œåœ¨ç”Ÿç‰©æ ‡å¿—ç‰©.

OBJECTIVES: To explore the pathogenesis and potential biomarkers of atrial fibrillation based on bioinformatics. METHODS: Differentially expressed genes and module genes related to atrial fibrillation were obtained from GSE41177 and GSE79768 databases (a platform using Chinese-origin tissue samples) through differential expression analysis and weighted gene co-expression network analysis, and candidate hub genes were obtained by taking intersections, and hub genes were obtained after gender stratification. Subsequently, functional enrichment analysis and immune infiltration analysis were performed. Four machine learning models were constructed based on the hub genes, and the optimal model was selected to construct a prediction nomogram; the prediction ability of the nomogram was verified using calibration curves and decision curves. Finally, potential therapeutic drugs for atrial fibrillation were screened in the DGIdb database. RESULTS: A total of 67 differentially expressed genes and 65 module genes related to atrial fibrillation were identified, and functional enrichment analysis indicated that the pathogenesis of atrial fibrillation was closely related to inflammatory response, immune response, and immune and infectious diseases. Four hub genes (TYROBP, FCER1G, EVI2B and SOD2) with generalization and two genes specifically expressed in male (PILRA and SLC35G3) and female (HLA-DRA and GATP) patients with atrial fibrillation were obtained after gender-segregated screening. The extreme gradient boosting model had satisfactory diagnostic efficacy, and the nomogram constructed based on the hub genes, male significant variables (PILRA, SLC35G3 and SOD2), and female significant variables (FCER1G, SOD2 and TYROBP) had satisfactory predictive ability. Immune infiltration analysis demonstrated a disturbed immune infiltration microenvironment in atrial fibrillation with a higher abundance of plasma cells, neutrophils, and γδT cells, with a higher abundance of neutrophils in males and resting mast cells in females. Two potential drugs for the treatment of atrial fibrillation, namely, valproic acid and methotrexate, were obtained by database and literature screening. CONCLUSIONS: The pathogenesis of atrial fibrillation is closely related to inflammation and immune response, and the microenvironment of immune cell infiltration of cardiomyocytes in the atrial tissue of patients with atrial fibrillation is disordered. TYROBP, FCER1G, EVI2B and SOD2 serve as potential diagnostic biomarkers of atrial fibrillation; PILRA and SLC35G3 serve as potential specific diagnostic biomarkers of atrial fibrillation in the male population, which can effectively predict the risk of atrial fibrillation development and are also potential targets for the treatment of atrial fibrillation.

Stored RBC transfusions leads to the systemic inflammatory response syndrome in anemic murine neonates.

OBJECTIVE: RBC transfusions (RBCT) are life-saving treatment for premature and critically ill infants. However, the procedure has been associated with the development of systemic inflammatory response syndrome (SIRS) and potentially multiple organ dysfunction syndrome (MODS) in neonates. The present study aimed to investigate the mechanisms of RBCT-related SIRS in severely anemic murine neonates. METHODS: C57BL/6 (WT), TLR4-/- and myeloid-specific triggered myeloid receptor-1 (trem1)-/- mouse pups were studied in 4 groups (n = 6 each): (1) naïve controls, (2) transfused control, (3) anemic (hematocrit 20-24%) and (4) anemic with RBC transfused using our established murine model of phlebotomy-induced anemia (PIA) and RBC transfusion. Plasma was measured for quantifying inflammatory cytokines (IFN-γ, IL-1ß, TNF-α, IL-6, MIP-1α, MIP-1ß, MIP2 and LIX) using a Luminex assay. In vitro studies included (i) sensitization by exposing the cells to a low level of lipopolysaccharide (LPS; 500 ng/ml) and (ii) trem1-siRNA transfection with/without plasma supernatant from stored RBC to assess the acute inflammatory response through trem1 by qRT-PCR and immunoblotting. RESULTS: Anemic murine pups developed cytokine storm within 2 h of receiving stored RBCs, which increased until 6 h post-transfusion, as compared to non-anemic mice receiving stored RBCTs ("transfusion controls"), in a TLR4-independent fashion. Nonetheless, severely anemic pups had elevated circulating endotoxin levels, thereby sensitizing circulating monocytes to presynthesize proinflammatory cytokines (IFN-γ, IL-1ß, TNF-α, IL-6, MIP-1α, MIP-1ß, MIP2, LIX) and express trem1. Silencing trem1 expression in Raw264.7 cells mitigated both endotoxin-associated presynthesis of proinflammatory cytokines and the RBCT-induced release of inflammatory cytokines. Indeed, myeloid-specific trem1-/- murine pups had significantly reduced evidence of SIRS following RBCTs. CONCLUSION: Severe anemia-associated low-grade inflammation sensitizes monocytes to enhance the synthesis of proinflammatory cytokines and trem1. In this setting, RBCTs further activate these monocytes, thereby inducing SIRS. Inhibiting trem1 in myeloid cells, including monocytes, alleviates the inflammatory response associated with the combined effects of anemia and RBCTs in murine neonates.