The African swine fever virus (ASFV), a complex DNA virus belonging to the Asfarviridae family, is a significant threat to the global swine industry because of its high mortality rates and impact on international trade. The establishment of a stable and efficient cell culture model of ASFV in vitro is helpful for the development of effective vaccines. Several passaged cell lines supporting ASFV replication have been reported to meet the scientific purpose of serial passage of ASFV to a certain extent, but it remains to be determined whether gene expression is lost or whether immunogenicity changes after serial passage of the virus. It is also unclear these edited cell lines how to affect ASFV replication. In our previous study, 3D4/21 cells were transduced with a lentivirus packaging system to express the BD1/2 domain of bromodomain-containing protein 4 (BRD4-BD1/2) and establish a 3D4/21-BD1/2 cell line, which efficiently increased ASFV replication. In this study, the role of bromodomain-containing protein 4 (BRD4), particularly its BD1/2 domains,in enhancing ASFV replication was investigated using an engineered 3D4/21 cell line. Through RNA-Seq transcriptomic analysis, we revealed that the host BRD4 protein facilitates ASFV infection and suppresses key transcription factors (CDK9 and p-CDK9) and inflammatory cytokine expression by downregulating transcriptional regulatory signaling pathways and suppressing innate immune responses. This dual mechanism of BRD4-BD1/2 in promoting ASFV immune evasion and adaptation underscores the virus's strategic exploitation of host epigenetic factors. These findings provide valuable insights into viral pathogenesis and identify potential therapeutic targets, paving the way for future antiviral strategies.

AiiO-AIO6 is a quorum-sensing quenching enzyme that could decrease the virulence of pathogenic bacteria, and improve animal immunity. However, the precise regulatory mechanism of AiiO-AIO6 on intestinal immunity remains unknown. Thus, this study aimed to reduce this knowledge gap. After feeding with graded levels of AIO-AIO6 (0.0 (un-supplemented group), 2.5, 5.0, 7.5, 10.0, and 12.5 U/g) for 70 days, juvenile grass carp was selected from each group for a 6-day Aeromonas hydrophila challenge test. Meanwhile, some other fish selected from un-supplemented control group were injected with saline as un-challenged control. Results showed that A. hydrophila infection increased enteritis morbidity, and caused intestinal inflammation in grass carp compared with saline group, while AiiO-AIO6 supplementation decreased enteritis morbidity, mitigated inflammatory cell infiltration, pyroptosis, and apoptosis in the intestine after A. hydrophila infection. Furthermore, both 5.0 and 7.5 U/g AiiO-AIO6 decreased gene expressions of tumor necrosis factor-α and interleukin-1β, and elevated gene expressions of transforming growth factor-β1 and IL-10, potentially associating with decreased NF-κB p65 and increased PPARγ signaling in the intestine. Supplementing 5.0 or 7.5 U/g AiiO-AIO6 also mitigated intestinal pyroptosis, as indicated by reduced mRNA levels of NLRP3, PYCARD, caspase-1, GSDME a, and GSDME b, and decreased protein levels of N-GSDME and IL-1β. Additionally, AiiO-AIO6 alleviated intestinal apoptosis, demonstrated by reduced gene expressions of pro-apoptotic genes apoptotic protease activating factor-1, Bcl-2 associated X protein, Fas ligand, and caspase-3, as well as c-Jun N-terminal kinase and mitogen-activated protein kinase p38, and elevated gene expressions of anti-apoptotic factors, B-cell lymphoma-2, myeloid cell leukemia 1, and inhibitor of apoptosis protein. Altogether, optimal levels of AiiO-AIO6 attenuated intestinal inflammation probably relating to down-regulated NF-κB signaling, and reduced NLRP3 and GSDME-mediated pyroptosis, and finally reduced apoptosis in the intestine of grass carp.

Chronic obstructive pulmonary disease (COPD) is a common and complex disease characterized by persistent airflow limitation and the presence of exacerbations, resulting in significant morbidity and mortality. Although the pathogenesis of COPD is multifactorial, airway inflammation plays a significant role in disease progression. Despite the advantages of non-pharmaceutical and pharmaceutical interventions that have significantly improved the symptom burden and exacerbation frequency in COPD, there is a lack of disease-modifying therapies that target the underlying disease mechanisms. Monoclonal antibodies (mAbs), a drug class that has improved treatment in severe asthma by blocking mediators of the type 2 (Th2) and allergic inflammatory cascades, are currently under investigation for their efficacy in COPD. Our review summarizes the evidence for the use of monoclonal antibodies in COPD and discusses current limitations and promising advances. Although targeting Th1 inflammation has failed to improve COPD outcomes, recent clinical trials have shown beneficial effects of monoclonal antibodies targeting Th2 inflammation, providing evidence for a personalized approach in COPD treatment.

Blockade of IL1RAP (interleukin 1 receptor associated protein) was recently shown to reduce atherosclerosis in mice, but the effect on human vascular cells is largely unknown. Targeting the IL1RAP coreceptor represents a novel strategy to block the IL1RAP-dependent cytokines IL (interleukin)-1, IL-33, and IL-36. In the present study, we aimed to evaluate the role of novel antibodies targeting IL1RAP to reduce the effects of IL-1β, IL-33, or IL-36γ in human vascular cells.

Expression of IL1RAP was observed in human atherosclerotic plaques by immunohistochemistry and microarray and in endothelial cells by flow cytometry. Endothelial cells were cultured with IL-1β, IL-33, or IL-36γ cytokines with or without IL1RAP antibodies and analyzed with Olink proteomics, ELISA, Western blot, and real-time quantitative polymerase chain reaction. The functional effect of IL1RAP antibodies on endothelial cells were analyzed with adhesion and permeability assays.

Olink proteomics showed inhibition of the inflammatory proteins LIF (leukemia inhibitory factor), OPG (osteoprotegerin), CCL4 (C-C motif chemokine ligand 4), and MCP-3 (monocyte chemoattractant protein 3) by IL1RAP-blockade in endothelial cells after IL-1β stimulation. In addition, the IL1RAP antibodies inhibited IL-1β, and IL-33 induced IL-6 and IL-8 secretion. Secretion of MCP-1 (monocyte chemoattractant protein 1) was induced by IL-1β, IL-33, and IL-36γ, and subsequently was inhibited by IL1RAP antibodies. Similar effects were found on mRNA expression level. Endothelial expression of the adhesion markers ICAM1, VCAM1, and SELE were significantly reduced by IL1RAP antibodies, and neutrophil adhesion to endothelial cells induced by IL-1β and IL-33 was reduced by IL1RAP blockade. In human atherosclerotic lesions, IL1RAP expression correlated with markers of inflammation like IL6, IL8, and MCP1.

IL1RAP-targeting antibodies can reduce the expression of inflammatory cytokines and markers of adhesion in endothelial cells, which may be of importance for future putative targeted treatments against cardiovascular disease.

The kidneys are crucial for filtering blood, managing overall body water, electrolyte, and acid-base balance, and regulating blood pressure. They remove metabolic waste products, toxins, and drugs. In addition, they limit inflammation by clearing cytokines and reduce immune cell activation by removing bacterial components. Dendritic cells (DCs) in the kidney maintain peripheral tolerance. About 85% of filtered water is reabsorbed by the proximal tubule, exposing distal nephron cells to high concentrations of low molecular weight antigens. These antigens are captured by DCs, helping to inactivate potentially autoreactive T cells and maintain tolerance to circulating antigens. In kidney failure, immune function is severely compromised due to the retention of toxins and cytokines, which activate immune cells and increase systemic inflammation. The kidneys are also vulnerable to immune-mediated diseases. Loss of immune homeostasis, characterized by over- or under-activity of the immune response, can adversely affect kidney function. With advances in immunology and cellular biology, biologic therapies targeting various pathways involved in the pathophysiology of kidney diseases are being developed. In this review, the immunologic aspects of kidney diseases and focus on cytokine-based therapies that may hold promise for the treatment of kidney diseases in the future will be presented.

Although several estrogen receptor β (ERβ) agonists have been reported to alleviate IBD, the pivotal mechanism remains obscure.

To examine the effects and mechanisms of ERβ activation on cytokine/chemokine networks in colitis mice.

Dextran sulfate sodium salt (DSS) and trinitro-benzene-sulfonic acid (TNBS) were used to induce mouse colitis model. Multiple molecular biological methods were employed to evaluate the severity of mouse colitis and the level of cytokine and/or chemokine.

Bioinformatics analysis, ELISA and immunofluorescence results showed that the targeted cytokines and/or chemokines associated with ERβ expression and activation is IL-1β, and the anti-colitis effect of ERβ activation was significantly attenuated by the overexpression of AAV9-IL-1β. Immunofluorescence analysis indicated that ERβ activation led to most evident downregulation of IL-1β expression in colonic macrophages as compared to monocytes and neutrophils. Given the pivotal roles of NLRP3, NLRC4, and AIM2 inflammasome activation in the production of IL-1β, we examined the influence of ERβ activation on inflammasome activity. ELISA and WB results showed that ERβ activation selectively blocked the NLRP3 inflammasome assembly-mediated IL-1β secretion. The calcium-sensing receptor (CaSR) and calcium signaling play crucial roles in the assembly of the NLRP3 inflammasome. WB and immunofluorescence results showed that ERβ activation reduced intracellular CaSR expression and calcium signaling in colonic macrophages. Combination with CaSR overexpression plasmid reversed the suppressive effect of ERβ activation on NLRP3 inflammasome assembly, and counteracting the downregulation of IL-1β secretion.

Our research uncovers that the anti-colitis effect of ERβ activation is accomplished through the reduction of IL-1β levels in colonic tissue, achieved by specifically decreasing CaSR expression in macrophages to lower intracellular calcium levels and inhibit NLRP3 inflammasome assembly-mediated IL-1β production.

Nerve injury is a significant cause of postherpetic neuralgia (PHN). It is marked by upregulated expression of cytokines secreted by immune cells such as tumor necrosis factor alpha, interleukin 1 beta (IL-1β), IL-6, IL-18, and IL-10. In neuropathic pain (NP) due to nerve injury, cytokines are important for the induction of neuroinflammation, activation of glial cells, and expression of cation channels. The release of chemokines due to nerve injury promotes immune cell infiltration, recruiting inflammatory cytokines and further amplifying the inflammatory response. The resulting disequilibrium in neuroimmune response and neuroinflammation leads to a reduction of nerve fibers, altered nerve excitability, and neuralgia. PHN is a typical NP and cytokines may induce PHN by promoting central and peripheral sensitization. Currently, treating PHN is challenging and research on the role of cytokine signaling pathways in PHN is lacking. This review summarizes the potential mechanisms of cytokine-mediated PHN and discusses the cytokine signaling pathways associated with the central and peripheral sensitization of PHN. By elucidating the mechanisms of cytokines, the cells and molecules that regulate cytokines, and their signaling systems in PHN, this review reveals important research developments regarding cytokines and their signaling pathways mediating PHN, highlighting new targets of action for the development of analgesic drugs.

Intervertebral disc degeneration (IVDD) is a prevalent musculoskeletal disorder characterized by the deterioration of nucleus pulposus (NP) cells, leading to significant impairments in patients' quality of life. Elucidating the molecular mechanisms underlying IVDD is essential for developing effective therapeutic strategies. In this study, we utilized weighted gene co-expression network analysis to identify key module eigengenes (MEs) from the GSE124272 dataset, combined with differential gene expression analysis to pinpoint differentially expressed genes (DEGs). Functional enrichment analysis revealed that MEs were primarily associated with lipid metabolism and immune response, while DEGs were enriched in immune response and cell proliferation pathways. By integrating MEs, DEGs, and ferroptosis-related genes, we identified six hub genes (acyl-CoA synthetase long-chain family member 1 [ACSL1], BACH1, CBS, CP, AKR1C1, and AKR1C3). Consensus clustering analysis classified samples into two immune-related subgroups, C1 and C2, with single-sample gene set enrichment analysis demonstrating distinct immune scores between the subgroups. Notably, ACSL1 showed the strongest correlation with immune cell infiltration and was significantly up-regulated in the C1 subgroup, which exhibited higher immune scores. In vitro experiments confirmed elevated ACSL1 expression in an IL-1β-induced degenerative NP cell model. Silencing ACSL1 improved cell viability, reduced apoptosis, and restored mitochondrial membrane potential, alongside significant changes in intracellular Fe2+, malondialdehyde, and glutathione levels. In vivo experiments further validated increased ACSL1 expression in intervertebral disc tissues of IVDD rats. Collectively, these findings highlight ACSL1 as a potential biomarker for the early diagnosis of IVDD and a promising therapeutic target.

Angelica sinensis polysaccharide (ASP) alleviated Rheumatoid arthritis (RA), but whether the relief was attributed to ASP itself or its microbial metabolites remained unclear. We characterized the main fraction of ASP (ASP-2pb) as a polysaccharide with molecular weight of 92.02 kDa. It contained approximately 48 repeating units of →6)-β-D-Galp-(1 → 3)-4-OMe-β-D-Galp-(1 → 4)-α-D-GalpA-(1 → 6)-β-D-Galp-(1 → 3)-4-OMe-β-D-Galp-(1→3)-β-D-Galp-(1 → 3)-β-D-Galp-(1 → 3)-β-D-Galp-(1 → with branches of Araf and Galp. Using ASP-2pb as intervention, the symptoms of RA in rats including joint swelling and inflammation were alleviated. Pseudo-germ-free animal test confirmed the necessity of specific gut bacteria during this alleviation. Bacteria such as Candidatus_Saccharimonas, Lactobacillus, Bifidobacterium, Faecalibaculum, Parvibacter, Ruminococcus_torques_group, Fournierella and Alloprevotella ought to be the key bacteria. Metabolites generated by these gut bacteria such as myristoleic acid, cuminaldehyde, 4-deoxypyridoxine and galactosylhydroxylysine, should be the key to RA remission. Therefore, specific metabolites were the consequence of the interaction between ASP-2pb and specific intestinal bacteria, and were responsible for the RA improvement.

One of the primary healthcare problems in the world today is tuberculosis (TB), a chronic infectious illness brought on by Mycobacterium tuberculosis (M. tuberculosis). A distinct family of PE_PGRS proteins, encoded by the M. tuberculosis genome, has attracted more attention because of their involvement in immune evasion and bacterial pathogenicity. Nevertheless, the specific functions and mechanisms of action for the majority of PE_PGRS proteins remain largely unexplored. This study focuses on the Rv2741 (PE_PGRS47) gene, which is exclusively present in pathogenic mycobacteria. To examine the function of Rv2741 in host-pathogen interactions, we created recombinant strains of Mycobacterium smegmatis (M. smegmatis) that expressed the M. tuberculosis Rv2741 gene. IL-1α was found to be a key mediator of host response modulation by Rv2741. Rv2741 downregulates the secretion of IL-1α and inhibits the MAPK signaling pathway, particularly the p38 and ERK1/2 pathways, thereby cooperatively inhibiting macrophage autophagy and apoptosis. Meanwhile, the decrease in IL-1α secretion directly leads to changes in the cytokine secretion pattern and a reduction in nitric oxide (NO) production. This multifaceted regulatory mechanism ultimately favors the survival of M. smegmatis in macrophages. This research significantly expands our understanding of Rv2741 function, revealing its crucial role as a multifunctional virulence factor in the immune evasion of M. tuberculosis.

Cyclooxygenase-2 (COX-2) is a key enzyme in the biosynthesis of prostaglandins and plays a special role in the process of inflammatory response. COX-2 is a target of non-steroidal anti-inflammatory drugs (NSAIDs), which can effectively relieve inflammation, pain and fever responses by inhibiting COX-2. Despite the significant study progress of inhibitors targeting COX-2, the development of COX-2 degraders remains insufficient. Proteolysis targeting chimaeras (PROTACs) have recently emerged as a fascinating technology for targeted protein degradation and drug discovery. In this report, we present the design, synthesis and detection of aspirin-based PROTACs that demonstrate effective ubiquitin-proteasome pathway degradation of COX-2 in lipopolysaccharide-stimulated RAW264.7 cells, and the aspirin-based negative PROTACs does not promote the degradation of COX-2. Moreover, we show AspPROTACs could significantly affect proteasome degradation and inflammatory signaling pathways through quantitative proteomic data analysis. These COX-2 degraders offer valuable chemical tools and novel insights for research in anti-inflammatory drugs.

Skin flaps are often used to repair wounds and improve a patient's appearance, particularly after severe burns. Although skin flaps are widely used, they are prone to necrosis, which poses a major clinical challenge. Tyrosol is a natural phenolic antioxidant found in olive oil that has anti-inflammatory, anti-apoptotic, antioxidant, and pro-angiogenic properties. Despite the recognition of these properties, no studies have investigated the effects of tyrosol on flap survival, although tyrosol significantly reduced flap edema and the necrotic area. In a rat study using the McFarland random flap model, gelatin lead oxide angiography showed that angiogenesis was increased significantly in high- and low-dose tyrosol groups. These immunohistochemistry findings highlight the impact of tyrosol on the inflammatory response and angiogenesis, underscoring its potential significance in flap survival. Western blot analysis showed that the expression of p38, NF-κB, and BAX was significantly down-regulated, while that of Bcl-2 was significantly up-regulated, in the high- and low-dose tyrosol groups. This modulation of key signaling pathways and apoptotic proteins not only validates the impact of tyrosol but also reinforces its role in providing protection, thus promoting flap survival. In summary, tyrosol may inhibit inflammation, oxidative stress, and apoptosis by downregulating the p38-NF-κB signaling pathway and promoting angiogenesis, thereby enhancing skin flap survival.

This study explored sex differences between dietary inflammatory index (DII) and cancer prognosis and their mechanisms. We hypothesized that association between dietary inflammatory index and cancer prognosis differs by sex. The study included 2874 adults with cancer from the National Health and Nutrition Examination Survey covering 1999 to 2014. Mortality status was linked to National Death Index mortality data through 31 December 2019. Cox proportional hazards regression models were applied to calculate hazard risk and 95% confidence intervals (Cis) in male patients and female patients. Sex-specific cancer and nonsex-specific cancer subgroup analyses were performed, and the role of C-reactive protein in sex differences was analyzed. The Cancer Genome Atlas pan-cancer transcriptome data were combined to explore the biological mechanisms of the sex differences. Multivariate Cox regression showed higher DII in male patients correlated with increased all-cause mortality (hazard risk highest vs lowest quartile = 1.57 [95% confidence intervals 1.24-1.98]; P for trend <.01), but not in female patients (P = .44). For sex-specific cancers, higher DII potentially correlated with increased mortality in prostate cancer (unadjusted P for trend = .04), but not in breast (P = .83), ovarian (P = .49), or cervical cancers (P = .91). In melanoma and colon cancer, higher DII correlated with increased mortality in male patients but not female patients. Serum C-reactive protein, interleukin-1 binding, interleukin-35 pathway, and programmed cell death protein 1 pathway may contribute to these sex differences. In conclusion, sex differences exist between DII and mortality risk in cancer patients.

Myocardial infarction (MI), a severe cardiovascular condition, is typically triggered by coronary artery disease, resulting in ischemic damage and the subsequent necrosis of the myocardium. Macrophages, known for their remarkable plasticity, are capable of exhibiting a range of phenotypes and functions as they react to diverse stimuli within their local microenvironment. In recent years, there has been an increasing number of studies on the regulation of macrophage behavior based on tissue engineering strategies, and its regulatory mechanisms deserve further investigation. This review first summarizes the effects of key regulatory factors of engineered biomaterials (including bioactive molecules, conductivity, and some microenvironmental factors) on macrophage behavior, then explores specific methods for inducing macrophage behavior through tissue engineering materials to promote myocardial repair, and summarizes the role of macrophage-host cell crosstalk in regulating inflammation, vascularization, and tissue remodeling. Finally, we propose some future challenges in regulating macrophage-material interactions and tailoring personalized biomaterials to guide macrophage phenotypes.

Background: Ouabain is a steroid hormone that binds to the sodium pump (Na+, K+-ATPase) at physiological (nanomolar) concentrations, activating different signaling pathways. This interaction has been shown to prevent the axotomy-induced death of retinal ganglion cells (RGCs), although the underlying mechanisms remain unclear. Objective: In this study, we investigated potential mechanisms by which ouabain promotes RGC survival using primary cultures of rat neural retina. Results: Our findings indicate that ouabain regulates brain-derived neurotrophic factor (BDNF) signaling in retinal cells via matrix metalloproteinase-9-mediated processing of proBDNF to mature BDNF (mBDNF) and by increasing the phosphorylation of the mBDNF receptor, tropomyosin-related receptor kinase B. Ouabain also enhances the maturation of interleukin (IL)-1β through the increased activation of caspase-1, which mediates the processing of proIL-1β into IL-1β, and transiently upregulates both IL-1 receptor and IL-1 receptor antagonist (IL-1Ra). Treatment using either IL-1β or IL-1Ra alone is sufficient to enhance RGC survival similarly to that achieved with ouabain. Finally, we further show that ouabain prevents RGC death through a complex signaling mechanism shared by BDNF and IL-1β, which includes the activation of the Src and protein kinase C pathways. Conclusions: Collectively, these results suggest that ouabain stimulates the maturation and signaling of both BDNF and IL-1β, which act as key mediators of RGC survival.

Epidemiological surveys indicate an increasing incidence of type 2 diabetes mellitus (T2DM) among children and adolescents worldwide. Due to rapid disease progression, severe long-term cardiorenal complications, a lack of effective treatment strategies, and substantial socioeconomic burdens, it has become an urgent public health issue that requires management and resolution. Adolescent T2DM differs from adult T2DM. Despite a significant increase in our understanding of youth-onset T2DM over the past two decades, the related review and evidence-based content remain limited.

To visualize the hotspots and trends in pediatric and adolescent T2DM research and to forecast their future research themes.

This study utilized the terms "children", "adolescents", and "type 2 diabetes", retrieving relevant articles published between 1983 and 2023 from three citation databases within the Web of Science Core Collection (SCI, SSCI, ESCI). Utilizing CiteSpace and VoSviewer software, we analyze and visually represent the annual output of literature, countries involved, and participating institutions. This allows us to predict trends in this research field. Our analysis encompasses co-cited authors, journal overlays, citation overlays, time-zone views, keyword analysis, and reference analysis, etc.

A total of 9210 articles were included, and the annual publication volume in this field showed a steady growth trend. The United States had the highest number of publications and the highest H-index. The United States also had the most research institutions and the strongest research capacity. The global hot journals were primarily diabetes professional journals but also included journals related to nutrition, endocrinology, and metabolism. Keyword analysis showed that research related to endothelial dysfunction, exposure risk, cardiac metabolic risk, changes in gut microbiota, the impact on comorbidities and outcomes, etc., were emerging keywords. They have maintained their popularity in this field, suggesting that these areas have garnered significant research interest in recent years.

Pediatric and adolescent T2DM is increasingly drawing global attention, with genes, behaviors, environmental factors, and multisystemic interventions potentially emerging as future research hot spots.

Extranodal NK/T cell lymphoma (ENKTCL) is an extremely aggressive form of lymphoma and lacks of specific diagnostic markers. The study intended to unearth the role of interleukin-33 (IL-33) in ENKTCL. RT-qPCR was conducted to assess mRNA levels of ENKTCL tissues and cells, while western blot assay was performed for evaluating protein levels. Plate cloning experiment and transwell assay were employed to measure aggressiveness of ENKTCL. Tube formation assay was executed to determine the angiogenesis ability. Mice ENKTCL xenograft model was designed to probe the impacts of IL-33 in vivo. IL-33 and suppression of tumorigenicity 2 receptor (ST2, receptor of IL-33) were enhanced in ENKTCL. IL-33 inhibition suppressed viability, migration, and invasion of ENKTCL cells. Moreover, IL-33 knockdown restricted angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, Wnt/β-catenin pathway associated proteins (β-catenin, c-myc, and cyclin D1) were downregulated by loss of IL-33. However, these impacts were overturned by Wnt/β-catenin signaling agonist lithium chloride (LiCl). Additionally, IL-33 silencing exerted anti-tumor effect via Wnt/β-catenin pathway in vivo. Silencing of IL-33 inhibited ENKTCL tumorigenesis and angiogenesis by inactivating Wnt/β-catenin signaling pathway. As such, IL-33 might be a prospective treatment target for ENKTCL.

Diabetes mellitus remains a global challenge to public health as it results in non-healing chronic ulcers of the lower limb. These wounds are challenging to heal, and despite the different treatments available to improve healing, there is still a high rate of failure and relapse, often necessitating amputation. Chronic diabetic ulcers do not follow an orderly progression through the wound healing process and are associated with a persistent inflammatory state characterised by the accumulation of pro-inflammatory macrophages, cytokines and proteases. Photobiomodulation has been successfully utilised in diabetic wound healing and involves illuminating wounds at specific wavelengths using predominantly light-emitting diodes or lasers. Photobiomodulation induces wound healing through diminishing inflammation and oxidative stress, among others. Research into the application of photobiomodulation for wound healing is current and ongoing and has drawn the attention of many researchers in the healthcare sector. This review focuses on the inflammatory pathway in diabetic wound healing and the influence photobiomodulation has on this pathway using different wavelengths.

To meet the prodigious bioenergetic demands of the photoreceptors, glucose and other nutrients must traverse the retinal pigment epithelium (RPE), a polarised monolayer of cells that lie at the interface between the outer retina and the choroid, the principal vascular layer of the eye. Recent investigations have revealed a metabolic ecosystem in the outer retina where the photoreceptors and RPE engage in a complex exchange of sugars, amino acids, and other metabolites. Perturbation of this delicate metabolic balance has been identified in the aging retina, as well as in age-related macular degeneration (AMD), the leading cause of blindness in the Western world. Also common in the aging and diseased retina are elevated levels of cytokines, oxidative stress, advanced glycation end-products, increased growth factor signalling, and biomechanical stress - all of which have been associated with metabolic dysregulation in non-retinal cell types and tissues. Herein, we outline the role of these factors in retinal homeostasis, aging, and disease. We discuss their effects on glucose, mitochondrial, lipid, and amino acid metabolism in tissues and cell types outside the retina, highlighting the signalling pathways through which they induce these changes. Lastly, we discuss promising avenues for future research investigating the roles of these pathological conditions on retinal metabolism, potentially offering novel therapeutic approaches to combat age-related retinal disease.

Schizophrenia is characterized by symptoms such as delusions, hallucinations, and avolition. The diagnosis is clinical, based on interviews and the main treatment involves antipsychotics. Currently, given the lack of clinically applicable biomarkers for schizophrenia, there is no molecular test based on its biological mechanisms to assist psychiatrists either in the prediction or diagnosis of the disorder, nor to measure medication efficacy. This scoping review assessed original articles in English about protein biomarkers for schizophrenia with samples that could be used in a clinical context, classifying them into diagnosis, prognosis, therapeutics, risk for psychosis, and side-effects. The search was conducted on PubMed and key findings were inserted on a summary table. We discussed the methodologies used in these papers, suggested protein panels for validation in longitudinal research, and proposed a hypothesis to explain the observed variability in results. This heterogeneity is explored in light of the debated validity of this construct, applying recent discussions and the disorder's history. Our data suggest that there is insufficient evidence to integrate protein biomarkers into clinical psychiatry for schizophrenia, not due to study quality, but possibly due to flaws in the current diagnostic system. We propose exploring alternative categorization systems.

Liver fibrosis is a progressive scarring process primarily caused by chronic inflammation and injury, often closely associated with viral hepatitis, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), drug-induced liver injury, and autoimmune liver disease (AILD). Currently, there are very few clinical antifibrotic drugs available, and effective targeted therapy is lacking. Recently, emerging antifibrotic drugs and immunomodulators have shown promising results in animal studies, and some have entered clinical research phases. This review aims to systematically review the molecular mechanisms underlying liver fibrosis, focusing on advancements in drug treatments for hepatic fibrosis. Furthermore, since liver fibrosis is a progression or endpoint of many diseases, it is crucial to address the etiological treatment and secondary prevention for liver fibrosis. We will also review the pharmacological treatments available for common hepatitis leading to liver fibrosis.

The purpose of this study was to determine the M1/M2 macrophage ratio in concentrated bone marrow aspirate (cBMA) in patients undergoing surgical intervention augmented with cBMA for osteochondral lesions of the talus (OLTs).

Samples of peripheral blood (PB), bone marrow aspirate (BMA), and cBMA were collected during the procedure. The samples were analyzed by automated cell counting and multicolor fluorescence-activated cell sorting with specific antibodies recognizing monocytes (CD14+ CD16+) and the M1 (CD86+) and M2 (CD163+CD206+) populations within that monocyte population. Cytokine concentrations within the samples were evaluated with enzyme-linked immunosorbent assay (ELISA). The composition of cBMA was compared between 2 commercially available BMA concentration systems.

Thirty-eight patients with a mean age of 43.2 ± 10.1 years old undergoing a surgical procedure for the treatment of OLTs involving the use of cBMA were included. cBMA had a mean fold increase of 4.7 for all white blood cells, 6.1 for monocytes, 7.9 for lymphocytes, 2.4 for neutrophils, and 9.6 for platelets when compared to BMA. The mean M1/M2 ratio for PB, BMA, and cBMA was 15.2 ± 12.0, 20.8 ± 13.3, and 22.1 ± 16.0, respectively. There was a statistically significant higher concentration of interleukin-1 receptor antagonist (IL-1Ra) in the cBMA sample (8243.3 ± 14,837.4 pg/mL) compared to both BMA (3143.0 ± 2218.5 pg/mL) and PB (1847.5 ± 1520.4 pg/mL) samples. The IL-1Ra/IL-1β ratio for PB, BMA, and cBMA was 790.6 ± 581.9, 764.7 ± 675.2, and 235.7 ± 192.1, respectively. There was no difference in the cBMA M1/M2 ratio (19.0 ± 11.1 vs 24.0 ± 18.3) between the Magellan (Isto Biologics, Hopkinton, Massachusetts) and Angel systems (Arthrex Inc, Naples, Florida).

This prospective study found that the M1/M2 ratio in cBMA was 22.1 ± 16.0, with significant patient to patient variation observed. Overall, there was no statistically significant difference in the M1/M2 ratio across PB, BMA, and cBMA samples. This is the first study to characterize the macrophage subpopulation within cBMA, which may have significant clinical implications in future studies.

Preeclampsia is a severe obstetrical syndrome which contributes to 10-15% of all maternal deaths. Although the mechanisms underlying systemic damage in preeclampsia-such as impaired placentation, endothelial dysfunction, and immune dysregulation-are well studied, the initial triggers of the condition remain largely unknown. Furthermore, although the pathogenesis of preeclampsia begins early in pregnancy, there are no early diagnostics for this life-threatening syndrome, which is typically diagnosed much later, after systemic damage has already manifested. Here, we performed deep metagenomic sequencing and multiplex immunoassays of vaginal samples collected during the first trimester from 124 pregnant individuals, including 62 who developed preeclampsia with severe features. We identified multiple significant associations between vaginal immune factors, microbes, clinical factors, and the early pathogenesis of preeclampsia. These associations vary with BMI, and stratification revealed strong associations between preeclampsia and Bifidobacterium spp., Prevotella timonensis, and Sneathia vaginalis. Finally, we developed machine learning models that predict the development of preeclampsia using this first trimester data, collected ~5.7 months prior to clinical diagnosis, with an auROC of 0.78. We validated our models using data from an independent cohort (MOMS-PI), achieving an auROC of 0.80. Our findings highlight robust associations among the vaginal microbiome, local host immunity, and early pathogenic processes of preeclampsia, paving the way for early detection, prevention and intervention for this devastating condition.

Osteomyelitis is a bone inflammation initiated by invading pathogens. Macrophages and inflammation play essential roles in osteomyelitis. F-Box and WD repeat domain containing 7 (Fbxw7) is a tumour suppressor and E3 ubiquitin ligase. In the present study, the potential roles of Fbxw7 in osteomyelitis were explored. The mRNA level of Fbxw7 was measured in bone marrow cells from patients with osteomyelitis and Staphylococcus aureus (S. aureus)-infected macrophages. The conditional knockout mice with Fbxw7 deficiency in myeloid cells were generated. The expression of interleukin (IL)-6, IL-23a and nitric oxide synthase 2 (Nos2) was measured in S. aureus-infected Fbxw7-deficient bone marrow-derived macrophages (BMDMs). The body weight loss, bacterial burden, bone loss and formation and serum level of IL-6, IL-23 and TNF-α were measured in S. aureus-infected Fbxw7 conditional KO mice. The interacting partners of Fbxw7 were predicted using STRING and the interaction were tested. Elevated expression of Fbxw7 was observed in bone marrow cells from patients with osteomyelitis and in S. aureus-infected macrophages. The expression of IL-6, IL-23a and Nos2 was remarkably suppressed in S. aureus-infected Fbxw7-deficient BMDMs. Fbxw7 conditional knockout mice had less body weight loss, higher bacterial burden, less bone loss and formation and decreased serum level of cytokines. Fbxw7 interacted with MYB. S. aureus-infected Fbxw7-deficient BMDMs had higher level of MYB and less ubiquitination of MYB. Fbxw7 promotes osteomyelitis symptoms by regulating ubiquitination and stability of MYB.

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies. This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years. We used quantitative neuropathology to place donors along a disease pseudoprogression score. Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin+ inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells; and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb+ and Vip+ inhibitory neuron subtypes. These findings were replicated in other major AD studies.

Traumatic brain injury (TBI) is a global public health concern. It remains one of the leading causes of morbidity and mortality. TBI pathology involves complex secondary injury cascades that are associated with cellular and molecular dysfunction, including oxidative stress, coagulopathy, neuroinflammation, neurodegeneration, neurotoxicity, and blood-brain barrier (BBB) dysfunction, among others. These pathological processes manifest as a diverse array of clinical impairments. They serve as targets for potential therapeutic intervention not only in TBI but also in other diseases. Monoclonal antibodies (mAbs) have been used as key therapeutic agents targeting these mechanisms for the treatment of diverse diseases, including neurological diseases such as Alzheimer's disease (AD). MAb therapies provide a tool to block disease pathways with target specificity that may be capable of mitigating the secondary injury cascades following TBI. This article reviews the pathophysiology of TBI and the molecular mechanisms of action of mAbs that target these shared pathological pathways in a wide range of diseases. Publicly available databases for various applications of mAb therapy were searched and further classified to assess relevance to TBI pathology and evaluate current stages of development. The authors intend for this review to highlight the potential impact of current mAb technology within pathological TBI processes.

Haploinsufficiency of the nuclear receptor binding SET domain-containing protein 1 gene (NSD1) leads to a neurodevelopmental disorder known as Sotos syndrome (SOTOS). This study investigated the effects of NSD1 knockdown in glial cells. U87MG glioma cells were transfected with siRNA targeting NSD1, which resulted in morphological changes characteristic of activated astrocytes. These activated phenotypes were accompanied by specific activation of mitogen-activated protein kinase (MAPK) signaling pathways, particularly those mediated by p38 MAPK and c-Jun N-terminal kinase (JNK). Transcriptome analysis showed increased expression of proinflammatory cytokine genes, particularly interleukin (IL)-1α, IL-1β, and IL-6, following NSD1 knockdown. Treatment with MAPK inhibitors significantly reduced the cytokine induction caused by NSD1 knockdown, with the p38 MAPK inhibitor being more effective than the JNK inhibitor. These findings provide new insights into the role of NSD1 loss in neurological dysfunctions associated with SOTOS.

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.

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).

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.

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.

Natural products dispirocochlearoids A-C, which are meroterpenoids derived from Ganoderma fungi, feature a 6/6/5/6/6/6 ring system and exhibit selective COX-2 inhibitory activity. Herein, the concise total synthesis of the tetracyclic core structure of dispirocochlearoids A-C was achieved through an aldol reaction/cyclization/deprotection/cyclization cascade sequence. A series of simplified tetracyclic analogues was successfully constructed and their anti-inflammatory activity was further explored, with several tetracyclic analogues (such as compound 8ab) exhibiting strong inhibitory activity against IL-1β expression in lipopolysaccharide-stimulated bone marrow-derived macrophage cells (IC50 = 2.8 μM).

PEGylated liposomal doxorubicin (PLD) has effectively reduced the cardiac toxicity of free doxorubicin (DOX) due to its unique nanoscale properties. However, an unexpected accumulation of PLD in the skin has led to hand-foot syndrome (HFS), negatively impacting quality of life and psychological well-being. In this study, self-limiting HFS rat models were created to mimic human symptoms through varying dosing schedules and intensities of PLD. The effects of PLD formulation parameters on HFS were also investigated. The results demonstrated that replacing ammonium sulfate with citric buffer, increasing liposome size, or reducing DSPE-mPEG2000 modification density alleviated HFS. Additionally, liposomes without DSPE-mPEG2000 modification completely avoided HFS, suggesting that PEGylated phospholipid was the key formulation parameter contributing to PLD-induced HFS. Furthermore, the correlation between liposome pharmacokinetics and HFS indicated that PEGylation, rather than the extended circulation time of liposomes, may mediated PLD-related HFS. Better understanding of the formulation parameters that trigger HFS can guide reformulation strategies to mitigate or prevent this syndrome.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.

The human interleukin-1 receptor I (IL-1R1) is a cytokine receptor recognized by interleukin 1β (IL-1β), among other cytokines. Over activation of IL-1R1 has been implicated in various inflammatory conditions. This research aims to identify small-molecule inhibitors targeting the hIL1R1/IL1β interaction, employing a multi-task transfer learning approach for quantitative structure-activity relationship (QSAR) modelling. A comprehensive bioactivity dataset from functionally related proteins was utilised to build a robust ensemble machine learning model for predicting IC50 values against the target protein. Despite the availability of antibody-based therapies, the absence of orally available small-molecule inhibitors necessitates their development. By combining model predictions with docking and simulation approaches, the interleukin-1 receptor inhibitor (IRI-1) emerged as a lead compound. It potently inhibited human IL1-R1 with micromolar activity in THP-1 and Saos-2 cells and demonstrated good biocompatibility. Western blot analysis revealed that IRI-1 inhibits IL-1β-mediated phosphorylation of IL1-R1, JNK, IRAK-4, and ERK in THP-1 cells. Furthermore, molecular dynamics simulations confirmed the structural stability of the protein-ligand complexes. This study highlights the effectiveness of multi-task transfer learning approaches for building robust QSAR models against novel proteins or those with limited bioactivity data, such as hIL-1β/IL-1R1 protein.

Chronic liver disease leads to hepatocellular injury that triggers a pro-inflammatory state in several parenchymal and non-parenchymal hepatic cell types, ultimately resulting in liver fibrosis, cirrhosis, portal hypertension and liver failure. Thus, an improved understanding of inflammasomes - as key molecular drivers of liver injury - may result in the development of novel diagnostic or prognostic biomarkers and effective therapeutics. In liver disease, innate immune cells respond to hepatic insults by activating cell-intrinsic inflammasomes via toll-like receptors and NF-κB, and by releasing pro-inflammatory cytokines (such as IL-1β, IL-18, TNF-α and IL-6). Subsequently, cells of the adaptive immune system are recruited to fuel hepatic inflammation and hepatic parenchymal cells may undergo gasdermin D-mediated programmed cell death, termed pyroptosis. With liver disease progression, there is a shift towards a type 2 inflammatory response, which promotes tissue repair but also fibrogenesis. Inflammasome activation may also occur at extrahepatic sites, such as the white adipose tissue in MASH (metabolic dysfunction-associated steatohepatitis). In end-stage liver disease, flares of inflammation (e.g., in severe alcohol-related hepatitis) that spark on a dysfunctional immune system, contribute to inflammasome-mediated liver injury and potentially result in organ dysfunction/failure, as seen in ACLF (acute-on-chronic liver failure). This review provides an overview of current concepts regarding inflammasome activation in liver disease progression, with a focus on related biomarkers and therapeutic approaches that are being developed for patients with liver disease.