Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans.

Patients with decreased levels of CD18 (ß2 integrins) suffer from life-threatening bacterial and fungal infections. CD11b, the α subunit of integrin CR3 (CD11b/CD18, αMß2), is essential for mice to fight against systemic Candida albicans infections. Live elongating C. albicans activates CR3 in immune cells. However, the hyphal ligands that activate CR3 are not well defined. Here, we discovered that the C. albicans Als family proteins are recognized by the I domain of CD11b in macrophages. This recognition synergizes with the ß-glucan-bound lectin-like domain to activate CR3, thereby promoting Syk signaling and inflammasome activation. Dectin-2 activation serves as the "outside-in signaling" for CR3 activation at the entry site of incompletely sealed phagosomes, where a thick cuff of F-actin forms to strengthen the local interaction. In vitro, CD18 partially contributes to IL-1ß release from dendritic cells induced by purified hyphal Als3. In vivo, Als3 is vital for C. albicans clearance in mouse kidneys. These findings uncover a novel family of ligands for the CR3 I domain that promotes fungal clearance.

Sinomonas terricola sp. nov., a plant-beneficial bacterium isolated from litchi rhizosphere soil in Guangdong, China.

A novel plant-beneficial bacterium strain, designated as JGH33T, which inhibited Peronophythora litchii sporangia germination, was isolated on Reasoner's 2A medium from a litchi rhizosphere soil sample collected in Gaozhou City, Guangdong Province, PR China. Cells of strain JGH33T were Gram-stain-positive, aerobic, non-motile, bent rods. The strain grew optimally at 30-37 °C and pH 6.0-8.0. Sequence similarity analysis based on 16S rRNA genes indicated that strain JGH33T exhibited highest sequence similarity to Sinomonas albida LC13T (99.2 %). The genomic DNA G+C content of the isolate was 69.1 mol%. The genome of JGH33T was 4.7 Mbp in size with the average nucleotide identity value of 83.45 % to the most related reference strains, which is lower than the species delineation threshold of 95 %. The digital DNA-DNA hybridization of the isolate resulted in a relatedness value of 24.9 % with its closest neighbour. The predominant respiratory quinone of JGH33T was MK-9(H2). The major fatty acids were C15 : 0 anteiso (43.4 %), C16 : 0 iso (19.1 %) and C17 : 0 anteiso (19.3 %), and the featured component was C18 : 3 ω6c (1.01 %). The polar lipid composition of strain JGH33T included diphosphatidylglycerol, phosphatidylglycerol, dimannosylglyceride, phosphatidylinositol and glycolipids. On the basis of polyphasic taxonomy analyses data, strain JGH33T represents a novel species of the genus Sinomonas, for which the name Sinomonas terricola sp. nov. is proposed, with JGH33T (=JCM 35868T=GDMCC 1.3730T) as the type strain.

Druggability properties of a L309K mutation in the antibody CH2 domain.

In the early stages of antibody drug development, it is imperative to conduct a comprehensive assessment and enhancement of the druggability attributes of potential molecules by considering their fundamental physicochemical properties. This study specifically concentrates on the surface-exposed hydrophobic region of the candidate antibody aPDL1-WT and explores the effectiveness of the L309K mutation strategy. The resulting aPDL1-LK variant demonstrates a notable enhancement over the original antibody in addressing the issue of aggregation and formation of large molecular impurities under accelerated high-temperature conditions. The mutated molecule, aPDL1-LK, exhibits excellent physicochemical properties such as hydrophilicity, conformational stability, charge variant stability, post-translational modifications, and serum stability. In terms of biological function, aPDL1-LK maintains the same glycosylation pattern as the original antibody and shows no significant difference in affinity for antigen hPDL1 protein, CD16a-F158, CD64, CD32a-H131, and complement C1q, compared to aPDL1-WT. The L309K mutation results in an approximately twofold reduction in its affinity for CD16a-V158 and CD32a-R131. In vitro biological assays, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), reveal that the L309K mutation may decrease CD16a-V158-mediated ADCC activity due to the mutation-induced decrease in ligand affinity, while not affect CD32a-R131-mediated ADCP activity. In conclusion, the L309K mutation offers a promising strategy to enhance the druggability properties of candidate antibodies.

Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity.

The multibasic furin cleavage site at the S1/S2 boundary of the spike protein is a hallmark of SARS-CoV-2 and plays a crucial role in viral infection. However, the mechanism underlying furin activation and its regulation remain poorly understood. Here, we show that GalNAc-T3 and T7 jointly initiate clustered O-glycosylations in the furin cleavage site of the SARS-CoV-2 spike protein, which inhibit furin processing, suppress the incorporation of the spike protein into virus-like-particles and affect viral infection. Mechanistic analysis reveals that the assembly of the spike protein into virus-like particles relies on interactions between the furin-cleaved spike protein and the membrane protein of SARS-CoV-2, suggesting a possible mechanism for furin activation. Interestingly, mutations in the spike protein of the alpha and delta variants of the virus confer resistance against glycosylation by GalNAc-T3 and T7. In the omicron variant, additional mutations reverse this resistance, making the spike protein susceptible to glycosylation in vitro and sensitive to GalNAc-T3 and T7 expression in human lung cells. Our findings highlight the role of glycosylation as a defense mechanism employed by host cells against SARS-CoV-2 and shed light on the evolutionary interplay between the host and the virus.

Nanomedicine-based disulfiram and metal ion co-delivery strategies for cancer treatment.

Disulfiram (DSF) is a second-line drug for the clinical treatment of alcoholism and has long been proven to be safe for use in clinical practice. In recent years, researchers have discovered the cancer-killing activity of DSF, which is highly dependent on the presence of metal ions, particularly copper ions. Additionally, free DSF is highly unstable and easily degraded within few minutes in blood circulation. Therefore, an ideal DSF formulation should facilitate the co-delivery of metal ions and safeguard the DSF throughout its biological journey before reaching the targeted site. Extensive research have proved that nanotechnology based formulations can effectively realize this goal by strategic encapsulation therapeutic agents within nanoparticle. To be more specific, this is accomplished through precise delivery, coordinated release of metal ions at the tumor site, thereby amplifying its cytotoxic potential. Beyond traditional co-loading techniques, innovative approaches such as DSF-metal complex and metal nanomaterials, have also demonstrated promising results at the animal model stage. This review aims to elucidate the anticancer mechanism associated with DSF and its reliance on metal ions, as well as to provide a comprehensive overview of recent advances in the arena of nanomedicine based co-delivery strategies for DSF and metal ion in the context of cancer therapy.

Association between late bedtime and obesity in children and adolescents: a meta-analysis.

Background: Short sleep duration has been related to obesity in children and adolescents. However, it remains unknown whether late bedtime is also associated with obesity and whether the association is independent of sleep duration. A meta-analysis was performed to address this issue. Methods: In order to accomplish the aim of the meta-analysis, a comprehensive search was conducted on databases including PubMed, Embase, and Web of Science to identify observational studies. The cutoff to determine late bedtime in children in this meta-analysis was consistent with the value used among the included original studies. As for obesity, it was typically defined as a body mass index (BMI) > 95th percentile of age and sex specified reference standards or the International Obesity Task Force defined age- and gender-specific cut-off of BMI. The Cochrane Q test was employed to evaluate heterogeneity among the included studies, while the I2 statistic was estimated. Random-effects models were utilized to merge the results, considering the potential impact of heterogeneity. Results: Tweleve observational studies with 57,728 participants were included. Among them, 6,815 (11.8%) were obese. Pooled results showed that late bedtime reported by the participants or their caregivers was associated with obesity (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 1.16-1.39, p < 0.001; I2 = 0%). Subgroup analysis showed consistent results in studies with (OR: 1.33, 95% CI: 1.04-1.70, p = 0.02) and without adjustment of sleep duration (OR: 1.27, 95% CI: 1.14-1.41, p < 0.001). Further subgroup analysis also showed that the association was not significantly affected by study location, design, age of the participants, or diagnostic methods for obesity (p for subgroup difference all >0.05). Conclusion: Late bedtime is associated with obesity in children and adolescents, which may be independent of sleep duration.

Opsonization Inveigles Macrophages Engulfing Carrier-Free Bilirubin/JPH203 Nanoparticles to Suppress Inflammation for Osteoarthritis Therapy.

Osteoarthritis (OA) is a chronic inflammatory disease characterized by cartilage destruction, synovitis, and osteophyte formation. Disease-modifying treatments for OA are currently lacking. Because inflammation mediated by an imbalance of M1/M2 macrophages in the synovial cavities contributes to OA progression, regulating the M1 to M2 polarization of macrophages can be a potential therapeutic strategy. Basing on the inherent immune mechanism and pathological environment of OA, an immunoglobulin G-conjugated bilirubin/JPH203 self-assembled nanoparticle (IgG/BRJ) is developed, and its therapeutic potential for OA is evaluated. After intra-articular administration, IgG conjugation facilitates the recognition and engulfment of nanoparticles by the M1 macrophages. The internalized nanoparticles disassemble in response to the increased oxidative stress, and the released bilirubin (BR) and JPH203 scavenge reactive oxygen species (ROS), inhibit the nuclear factor kappa-B pathway, and suppress the activated mammalian target of rapamycin pathway, result in the repolarization of macrophages and enhance M2/M1 ratios. Suppression of the inflammatory environment by IgG/BRJ promotes cartilage protection and repair in an OA rat model, thereby improving therapeutic outcomes. This strategy of opsonization involving M1 macrophages to engulf carrier-free BR/JPH203 nanoparticles to suppress inflammation for OA therapy holds great potential for OA intervention and treatment.

[Spatial Distribution Characteristics of PM2.5 and O3 in Beijing-Tianjin-Hebei Region Based on Time Series Decomposition].

Notably, clear spatial differences occur in the distribution of air pollution among cities in the Beijing-Tianjin-Hebei (BTH) Region. Clarifying the concentration distribution of PM2.5 and O3 at different time scales is helpful to formulate scientific and effective pollution prevention and control measures. Here, the concentrations of PM2.5 and O3 were decomposed using a seasonal-trend decomposition procedure based on the loess (STL) method; their long-term, seasonal, and short-term components were obtained; and their temporal and spatial distribution characteristics were studied. The results showed that the decrease in PM2.5 concentration in the BTH Region from 2017 to 2021 was higher than that of O3. There was a positive correlation between PM2.5 and O3 concentrations in spring and summer and a negative correlation in autumn and winter. The short-term component and seasonal component had the greatest contribution to PM2.5 and O3 concentrations, respectively. There were two principal components in the seasonal and short-term components of PM2.5 and the long-term and short-term components of O3, corresponding to the central and southern part of Hebei Province and the northern part of the BTH Region. Sub-regional distribution of PM2.5 and O3 in the BTH Region at different time scales were found. Compared with that in the original series, the long-term component could better reflect the evolution trend of PM2.5 and O3 concentrations, and the standard deviation (SD) of the seasonal component and short-term component could be used to measure the fluctuation in PM2.5 and O3 concentrations in various cities. The SD of the seasonal and short-term components of the PM2.5 concentration in every city in front of Taihang Mountain was higher, and the SD of the short-term component of the O3 concentration in Tangshan was the highest.

Unveiling the micronutrient-immunity puzzle in inactivated COVID-19 vaccination: A comprehensive analysis of circulating micronutrient levels and humoral responses in healthy adults.

While micronutrients are crucial for immune function, their impact on humoral responses to inactivated COVID-19 vaccination remains unclear. We investigated the associations between seven key micronutrients and antibody responses in 44 healthy adults with two doses of an inactivated COVID-19 vaccine. Blood samples were collected pre-vaccination and 28 days post-booster. We measured circulating minerals (iron, zinc, copper, and selenium) and vitamins (A, D, and E) concentrations alongside antibody responses and assessed their associations using linear regression analyses. Our analysis revealed inverse associations between blood iron and zinc concentrations and anti-SARS-CoV-2 IgM antibody binding affinity (AUC for iron: ß = -258.21, p < 0.0001; zinc: ß = -17.25, p = 0.0004). Notably, antibody quality presented complex relationships. Blood selenium was positively associated (ß = 18.61, p = 0.0030), while copper/selenium ratio was inversely associated (ß = -1.36, p = 0.0055) with the neutralizing ability against SARS-CoV-2 virus at a 1:10 plasma dilution. There was no significant association between circulating micronutrient concentrations and anti-SARS-CoV-2 IgG binding affinity. These findings suggest that circulating iron, zinc, and selenium concentrations and copper/selenium ratio, may serve as potential biomarkers for both quantity (binding affinity) and quality (neutralization) of humoral responses after inactivated COVID-19 vaccination. Furthermore, they hint at the potential of pre-vaccination dietary interventions, such as selenium supplementation, to improve vaccine efficacy. However, larger, diverse studies are needed to validate these findings. This research advances the understanding of the impact of micronutrients on vaccine response, offering the potential for personalized vaccination strategies.

C/EBPß: A transcription factor associated with the irreversible progression of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aß (ß-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPß in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment. AIMS: Several studies have demonstrated an elevation in the expression level of C/EBPß among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPß expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPß can be a new therapeutic target for AD. METHODS: A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded. RESULTS: Overexpression of C/EBPß exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO). DISCUSSION: The correlation between overexpression of C/EBPß and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPß regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPß overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS). CONCLUSION: The overexpression of C/EBPß accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPß plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPß could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.

RhIII-Catalyzed Direct Heteroarylation of Unactivated C(sp3)-H with N-Heteroaryl Boronates.

Disclosed herein is a rhodium(III)-catalyzed direct heteroarylation reaction between unactivated aliphatic C(sp3)-H bonds in 2-alkylpyridines and heteroaryl organoboron reagents. This catalytic protocol is compatible with various heterocyclic boronates containing ortho- and meta-pyridine, pyrazoles, furan, and quinoline with strong coordination capability. The achievement of this methodology provides an efficient route to build new C(sp3)-heteroaryl bonds.

Nasal vaccination of triple-RBD scaffold protein with flagellin elicits long-term protection against SARS-CoV-2 variants including JN.1.

Developing a mucosal vaccine against SARS-CoV-2 is critical for combatting the epidemic. Here, we investigated long-term immune responses and protection against SARS-CoV-2 for the intranasal vaccination of a triple receptor-binding domain (RBD) scaffold protein (3R-NC) adjuvanted with a flagellin protein (KFD) (3R-NC + KFDi.n). In mice, the vaccination elicited RBD-specific broad-neutralizing antibody responses in both serum and mucosal sites sustained at high level over a year. This long-lasting humoral immunity was correlated with the presence of long-lived RBD-specific IgG- and IgA-producing plasma cells, alongside the Th17 and Tfh17-biased T-cell responses driven by the KFD adjuvant. Based upon these preclinical findings, an open labeled clinical trial was conducted in individuals who had been primed with the inactivated SARS-CoV-2 (IAV) vaccine. With a favorable safety profile, the 3R-NC + KFDi.n boost elicited enduring broad-neutralizing IgG in plasma and IgA in salivary secretions. To meet the challenge of frequently emerged variants, we further designed an updated triple-RBD scaffold protein with mutated RBD combinations, which can induce adaptable antibody responses to neutralize the newly emerging variants, including JN.1. Our findings highlight the potential of the KFD-adjuvanted triple-RBD scaffold protein is a promising prototype for the development of a mucosal vaccine against SARS-CoV-2 infection.

Noncoding RNAs in skeletal development and disorders.

Protein-encoding genes only constitute less than 2% of total human genomic sequences, and 98% of genetic information was previously referred to as "junk DNA". Meanwhile, non-coding RNAs (ncRNAs) consist of approximately 60% of the transcriptional output of human cells. Thousands of ncRNAs have been identified in recent decades, and their essential roles in the regulation of gene expression in diverse cellular pathways associated with fundamental cell processes, including proliferation, differentiation, apoptosis, and metabolism, have been extensively investigated. Furthermore, the gene regulation networks they form modulate gene expression in normal development and under pathological conditions. In this review, we integrate current information about the classification, biogenesis, and function of ncRNAs and how these ncRNAs support skeletal development through their regulation of critical genes and signaling pathways in vivo. We also summarize the updated knowledge of ncRNAs involved in common skeletal diseases and disorders, including but not limited to osteoporosis, osteoarthritis, rheumatoid arthritis, scoliosis, and intervertebral disc degeneration, by highlighting their roles established from in vivo, in vitro, and ex vivo studies.

[Chemical constituents from roots of Kadsura heteroclita].

The dichloromethane fraction of Kadsura heteroclita roots was separated and purified by chromatographic techniques(e.g., silica gel, Sephadex LH-20, ODS, MCI column chromatography) and semi-preparative HPLC. Twenty compounds were isolated from K. heteroclita, and their structures were identified by NMR, MS, UV, and X-ray single crystal diffraction techniques. Twenty compounds were isolated from K. heteroclita, which were identified as xuetongdilactone G(1), mallomacrostin C(2), 3,4-seco(24Z)-cychmrt-4(28),24-diene-3,26-dioic acid 3-methyl ester(3), nigranoic acid(4), methyl ester schizanlactone E(5), schisandronic acid(6), heteroclic acid(7), wogonin(8),(2R,3R)-4'-O-methyldihydroquercetin(9), 15,16-bisnor-13-oxo-8(17),11E-labdadien-19-oic acid(10), stigmast-4-ene-6ß-ol-3-one(11), psoralen(12),(1R,2R,4R)-trihydroxy-p-menthane(13), homovanillyl alcohol(14), 2-(4-hydroxyphenyl)-ethanol(15), coniferaldehyde(16),(E)-7-(4-hydroxy-3-methoxyphenyl)-7-methylbut-8-en-9-one(17), acetovanillone(18), vanillic acid(19) and vanillin(20). Compound 1 is a new compound named xuetongdilactone G. Compounds 2-3 and 8-20 are isolated from K. heteroclita for the first time.

Multifunctional iron-apigenin nanocomplex conducting photothermal therapy and triggering augmented immune response for triple negative breast cancer.

Triple negative breast cancer (TNBC) presents a formidable challenge due to its low sensitivity to many chemotherapeutic drugs and a relatively low overall survival rate in clinical practice. Photothermal therapy has recently garnered substantial interest in cancer treatment, owing to its swift therapeutic effectiveness and minimal impact on normal cells. Metal-polyphenol nanostructures have recently garnered significant attention as photothermal transduction agents due to their facile preparation and favorable photothermal properties. In this study, we employed a coordinated approach involving Fe3+ and apigenin, a polyphenol compound, to construct the nanostructure (nFeAPG), with the assistance of ß-CD and DSPE-PEG facilitating the formation of the complex nanostructure. In vitro research demonstrated that the formed nFeAPG could induce cell death by elevating intracellular oxidative stress, inhibiting antioxidative system, and promoting apoptosis and ferroptosis, and near infrared spectrum irradiation further strengthen the therapeutic outcome. In 4T1 tumor bearing mice, nFeAPG could effectively accumulate into tumor site and exhibit commendable control over tumor growth. Futher analysis demonstrated that nFeAPG ameliorated the suppressed immune microenvironment by augmenting the response of DC cells and T cells. This study underscores that nFeAPG encompasses a multifaceted capacity to combat TNBC, holding promise as a compelling therapeutic strategy for TNBC treatment.

Emerging application of nanomedicine-based therapy in acute respiratory distress syndrome.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are serious lung injuries caused by various factors, leading to increased permeability of the alveolar-capillary barrier, reduced stability of the alveoli, inflammatory response, and hypoxemia. Despite several decades of research since ARDS was first formally described in 1967, reliable clinical treatment options are still lacking. Currently, supportive therapy and mechanical ventilation are prioritized, and there is no medication that can be completely effective in clinical treatment. In recent years, nanomedicine has developed rapidly and has exciting preclinical treatment capabilities. Using a drug delivery system based on nanobiotechnology, local drugs can be continuously released in lung tissue at therapeutic levels, reducing the frequency of administration and improving patient compliance. Furthermore, this novel drug delivery system can target specific sites and reduce systemic side effects. Currently, many nanomedicine treatment options for ARDS have demonstrated efficacy. This review briefly introduces the pathophysiology of ARDS, discusses various research progress on using nanomedicine to treat ARDS, and anticipates future developments in related fields.

Tomato plant growth promotion and drought tolerance conferred by three arbuscular mycorrhizal fungi is mediated by lipid metabolism.

Arbuscular mycorrhizal fungi (AMF) can promote plant growth and enhance plant drought tolerance with varying effect size among different fungal species. However, the linkage between the variation and the lipid metabolism, which is exclusively derived from plants, has been little explored thus far. Here, we established AM symbiosis between tomato (Solanum lycopersicum) plants and three AMF species (Rhizophagus intraradices, Funneliformis mosseae, Rhizophagus irregularis) under well watered (WW) or drought stressed (DS) conditions in pot experiment. The plant biomass, chlorophyll fluorescence Fv/Fm, shoot P content and mycorrhizal colonization were determined. Meanwhile, fatty acid (FA) profiles and relative expression of genes encoding for nutrition exchange (SlPT4, SlPT5, RAM2, STR/STR2) in roots were also monitored. DS significantly decreased plant biomass while AMF significantly increased it, with three fungal species varying in their growth promoting capacity and drought tolerance capacity. The growth promoting effect of R. irregularis was lower than those of R. intraradices and F. mosseae, and was associated with higher mycorrhizal colonization and more consumption of lipids. However, the drought tolerance capacity of R. irregularis was greater than those of R. intraradices and F. mosseae, and was associated with less decrease in mycorrhizal colonization and lipid content. We also found that AMF mediated plant drought tolerance via regulating both AM specific FAs and non-AM specific FAs in a complementary manner. These data suggest that lipid metabolism in AM plays a crucial role in plant drought tolerance mediated by AMF.

Flavonoid extracted from Epimedium attenuate cGAS-STING-mediated diseases by targeting the formation of functional STING signalosome.

Hyperactivation of the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway has been shown to be associated with the development of a variety of inflammatory diseases, and the discovery of an inhibitor of the cGAS-STING signalling pathway holds great promise in the therapeutic interventions. Epimedium flavonoid (EF), a major active ingredient isolated from the medicinal plant Epimedium, has been reported to have good anti-inflammatory activity, but its exact mechanism of action remains unclear. In the present study, we found that EF in mouse bone marrow-derived macrophages (BMDMs), THP-1 (Tohoku Hospital Pediatrics-1) as well as in human peripheral blood mononuclear cells (hPBMC) inhibited the activation of the cGAS-STING signalling pathway, which subsequently led to a decrease in the expression of type I interferon (IFN-ß, CXCL10 and ISG15) and pro-inflammatory cytokines (IL-6 and TNF-α). Mechanistically, EF does not affect STING oligomerization, but inhibits the formation of functional STING signalosome by attenuating the interaction of interferon regulatory factor 3 (IRF3) with STING and TANK-binding kinase 1 (TBK1). Importantly, in vivo experiments, EF has shown promising therapeutic effects on inflammatory diseases mediated by the cGAS-STING pathway, which include the agonist model induced by DMXAA stimulation, the autoimmune inflammatory disease model induced by three prime repair exonuclease 1 (Trex1) deficiency, and the non-alcoholic steatohepatitis (NASH) model induced by a pathogenic amino acid and choline deficiency diet (MCD). To summarize, our study suggests that EF is a potent potential inhibitor component of the cGAS-STING signalling pathway for the treatment of inflammatory diseases mediated by the cGAS-STING signalling pathway.

Pip5k1c expression in osteocytes regulates bone remodeling in mice.

Research background: The role of osteocytes in maintaining bone mass has been progressively emphasized. Pip5k1c is the most critical isoform among PIP5KIs, which can regulate cytoskeleton, biomembrane, and Ca2+ release of cells and participate in many processes, such as cell adhesion, differentiation, and apoptosis. However, its expression and function in osteocytes are still unclear. Materials and methods: To determine the function of Pip5k1c in osteocytes, the expression of Pip5k1c in osteocytes was deleted by breeding the 10-kb mouse Dmp1-Cre transgenic mice with the Pip5k1cfl/fl mice. Bone histomorphometry, micro-computerized tomography analysis, immunofluorescence staining and western blotting were used to determine the effects of Pip5k1c loss on bone mass. In vitro, we explored the mechanism by siRNA knockdown of Pip5k1c in MLO-Y4 cells. Results: Pip5k1c expression was decreased in osteocytes in senescent and osteoporotic tissues both in humans and mice. Loss of Pip5k1c in osteocytes led to a low bone mass in long bones and spines and impaired biomechanical properties in femur, without changes in calvariae. The loss of Pip5k1c resulted in the reduction of the protein level of type 1 collagen in tibiae and MLO-Y4 cells. Osteocyte Pip5k1c loss reduced the osteoblast and bone formation rate with high expression of sclerostin, impacting the osteoclast activities at the same time. Moreover, Pip5k1c loss in osteocytes reduced expression of focal adhesion proteins and promoted apoptosis. Conclusion: Our studies demonstrate the critical role and mechanism of Pip5k1c in osteocytes in regulating bone remodeling. The translational potential of this article: Osteocyte has been considered to a key role in regulating bone homeostasis. The present study has demonstrated that the significance of Pip5k1c in bone homeostasis by regulating the expression of collagen, sclerostin and focal adhesion expression, which provided a possible therapeutic target against human metabolic bone disease.

Bilirubin ameliorates osteoarthritis via activating Nrf2/HO-1 pathway and suppressing NF-κB signalling.

Osteoarthritis (OA) is a chronic degenerative joint disease that affects worldwide. Oxidative stress plays a critical role in the chronic inflammation and OA progression. Scavenging overproduced reactive oxygen species (ROS) could be rational strategy for OA treatment. Bilirubin (BR) is a potent endogenous antioxidant that can scavenge various ROS and also exhibit anti-inflammatory effects. However, whether BR could exert protection on chondrocytes for OA treatment has not yet been elucidated. Here, chondrocytes were exposed to hydrogen peroxide with or without BR treatment. The cell viability was assessed, and the intracellular ROS, inflammation cytokines were monitored to indicate the state of chondrocytes. In addition, BR was also tested on LPS-treated Raw264.7 cells to test the anti-inflammation property. An in vitro bimimic OA microenvironment was constructed by LPS-treated Raw264.7 and chondrocytes, and BR also exert certain protection for chondrocytes by activating Nrf2/HO-1 pathway and suppressing NF-κB signalling. An ACLT-induced OA model was constructed to test the in vivo therapeutic efficacy of BR. Compared to the clinical used HA, BR significantly reduced cartilage degeneration and delayed OA progression. Overall, our data shows that BR has a protective effect on chondrocytes and can delay OA progression caused by oxidative stress.