PM2.5-induced brain damage is related to systemic inflammation and oxidative stress, which can be caused by PM2.5 acting directly on the brain or indirectly by stimulating inflammation in the peripheral nervous system; however, the underlying pathological mechanisms are still unclear. Baicalin (BC) and geniposide glycosides (GD) are natural products that may exert neuroprotective effects by reducing inflammatory responses and oxidative damage.

SARS-CoV-2 has posed serious global health challenges not only because of the high degree of virus transmissibility but also due to its severe effects on the respiratory system, such as inducing changes in multiple organs through the ACE2 receptor. This virus makes changes to gene expression at the single-cell level and thus to cellular functions and immune responses in a variety of cell types. Previous studies have not been able to resolve these mechanisms fully, and so our study tries to bridge knowledge gaps about the cellular responses under conditions of infection. We performed single-cell RNA-sequencing of nasopharyngeal swabs from COVID-19 patients and healthy controls. We assembled a dataset of 32,588 cells for 58 subjects for analysis. The data were sorted into eight cell types: ciliated, basal, deuterosomal, goblet, myeloid, secretory, squamous, and T cells. Using machine learning, including nine feature ranking algorithms and two classification algorithms, we classified the infection status of single cells and analyzed gene expression to pinpoint critical markers of SARS-CoV-2 infection. Our findings show distinct gene expression profiles between infected and uninfected cells across diverse cell types, with key indicators such as FKBP4, IFITM1, SLC35E1, CD200R1, MT-ATP6, KRT13, RBM15, and FTH1 illuminating unique immune responses and potential pathways for viral spread and immune evasion. The machine learning methods effectively differentiated between infected and non-infected cells, shedding light on the cellular heterogeneity of SARS-CoV-2 infection. The findings will improve our knowledge of the cellular dynamics of SARS-CoV-2.

Low back pain after spine surgery is a major complication due to excessive epidural fibrosis, which compresses the lumbar nerve. Macrophage-myofibroblast transition (MMT) promoted epidural fibrosis in a mouse laminectomy model. Previously, we demonstrated that LincR-PPP2R5C regulated CD4 + T-cell differentiation. Here, we aimed to explore the roles and mechanisms of LincR-PPP2R5C in macrophages in epidural fibrosis. In M2 macrophages, the level of LincR-PPP2R5C was significantly decreased. Upon overexpression, LincR-PPP2R5C induced M1-macrophage polarization and reduced MMT. In contrast, LincR-PPP2R5C deficiency promoted M2-macrophage polarization and increased MMT. Mechanistically, LincR-PPP2R5C modulated the expression of α-SMA in macrophages via the PP2A signaling pathway. In vivo, LincR-PPP2R5C deficiency aggravated epidural fibrosis by enhancing MMT in a mouse model of laminectomy, and this effect was abolished in mice with macrophage depletion. Our study shed light on the effects of LincR-PPP2R5C on macrophage differentiation and MMT in epidural fibrosis.

Diabetes is an endocrine disorder characterized by abnormally elevated blood glucose levels. Diabetic patients often exhibit impaired wound healing capabilities, particularly in the lower limbs, which is one of the numerous complications of diabetes. This is a significant factor leading to recurrent inflammation, disability, and even amputation. The primary objective of this study is to explore the mechanism by which shikonin accelerates diabetic wound healing by modulating macrophage phenotypes, particularly its role in the MAPK signaling pathway. To this end, we used a diabetic rat model and analyzed the effects of shikonin on the wound healing process and macrophage polarization in both in vivo and in vitro experiments. Additionally, we used immunofluorescence staining and Western blot techniques to detect the expression levels of macrophage polarization markers and proteins related to the MAPK signaling pathway. The results verify that shikonin significantly accelerated wound healing in diabetic rats and inhibited the polarization of M1 macrophages, reducing the expression of pro-inflammatory factors, while promoting the polarization of M2 macrophages, increasing the expression of anti-inflammatory factors. This process was accompanied by the regulation of the MAPK signaling pathway, indicating that shikonin accelerates diabetic wound healing by regulating the MAPK signaling pathway to inhibit the inflammatory phenotype of macrophages, showing significant clinical application prospects.

Sepsis, a common and life-threatening condition often leading to multiple organ dysfunction, currently lacks a prognostic model based on ferroptosis-related genes (FRGs) for predicting clinical outcomes. In this study, we utilized the FerrDb database and GSE65682 dataset to evaluate the prognostic significance of FRGs in sepsis. Differential expression analysis identified 27 DE-FRGs, and Consensus clustering revealed three distinct FRG molecular subtypes in sepsis with notable differences in immune infiltration landscapes. Univariate and multivariate Cox regression, along with LASSO analysis, were employed to construct an FRG-based prognostic model, which indicated significantly better clinical outcomes for the low FRG score subgroup compared to the high FRG score subgroup. Validation through nomogram prediction models and independent prognostic analysis confirmed the accuracy of FRGs in assessing sepsis prognosis. Single-cell sequencing further demonstrated the distribution of the FRG prognostic signature across cellular subpopulations in sepsis samples. Functional experiments, including siRNA transfection, malondialdehyde (MDA) assays, Western blot, and reactive oxygen species (ROS) assays, revealed that TFRC plays a critical role in sepsis by inhibiting ferroptosis. These findings suggest that the FRG prognostic scoring model is a reliable predictor of sepsis prognosis, with TFRC identified as a key regulatory factor inhibiting ferroptosis in sepsis.

To determine the characteristic changes of peripheral blood T cells and identify potential biomarkers that associated with the clinical efficacy of combined immunotherapy and anti-angiogenic therapy in patients with advanced squamous non-small cell lung cancer (NSCLC).

Renal ischemia-reperfusion injury (IRI) is a prevailing manifestation of acute kidney injury (AKI) with limited treatment options. TRIM44 has emerged as a possible target for treatment due to its regulatory function in inflammatory pathways.

Neutrophils are the most abundant cell type in human blood and play a crucial role in the immune system and development of tumors. This review begins with the generation and development of neutrophils, traces their release from the bone marrow into the bloodstream, and finally discusses their role in the hepatocellular carcinoma (HCC) microenvironment. It elaborates in detail the mechanisms by which tumor-associated neutrophils (TANs) exert antitumor or protumor effects under the influence of various mediators in the tumor microenvironment. Neutrophils can exert antitumor effects through direct cytotoxic action. However, they can also accelerate the formation and progression of HCC by being recruited and infiltrated, promoting tumor angiogenesis, and maintaining an immunosuppressive microenvironment. Therefore, based on the heterogeneity and plasticity of neutrophils in tumor development, this review summarizes the current immunotherapies targeting TANs, discusses potential opportunities and challenges, and provides new insights into exploring more promising strategies for treating HCC.

As one of the largest organs of our human body, skeletal muscle has good research prospects in myasthenia gravis (MG), the symptoms of which include systemic skeletal muscle weakness. Skeletal muscle is composed of two types of muscle fibers. Different fiber subtypes can be converted into each other; however, the underlying mechanism is not yet clear. In this paper, we firstly established an experimental autoimmune myasthenia gravis (EAMG) rat model and found that the skeletal muscle fibers of the EAMG group were atrophied, with a change in the proportion of fiber subtypes, which switched from type IIa to type I in the EAMG group at the peak stage, as verified by histological and molecular analyses. Second-generation sequencing results predicted that the PI3K-Akt signaling pathway might be involved in the switch, and the mRNA expression levels of the PI3K-Akt pathway-related genesNr4a1, IL2rb, Col1A1 and Ddit4 were significantly different. In conclusion, this study indicates that the switch of muscle fiber subtypes in MG via the PI3K-Akt signaling pathway may be a potential target for the treatment of MG-related skeletal muscle atrophy in the future.

Midges are widely distributed globally. They can transmit numerous serious diseases as well as trigger an allergic reaction in the host. Their saliva contains a variety of proteins that act as sensitizers to stimulate the host's immune response, leading to IgE-mediated allergic symptoms.

SARS-CoV-2-specific CD8 cytotoxic T lymphocytes (CTLs) are crucial in viral clearance, disease progression, and reinfection control. However, numerous SARS-CoV-2 immunodominant CTL epitopes theoretically are still unidentified due to the genetic polymorphism of human leukocyte antigen class I (HLA-I) molecules.

The intestinal mucosa of ulcerative colitis patients expresses high levels of interleukin 34, and mice lacking IL-34 have more severe DSS-induced experimental colitis. There are no studies on the effects of directly upregulating intestinal IL-34 on experimental colitis in mice.

The immunoglobulin E (IgE) receptor FcεRI (Fc epsilon RI) plays a crucial role in allergic reactions. Recent studies have indicated that the interaction between FcεRIβ and the downstream protein phospholipase C beta 3 (PLCβ3) leads to the production of inflammatory cytokines. The aim of this study was to develop small molecules that inhibit the protein-protein interactions between FcεRIβ and PLCβ3 to treat allergic inflammation. Additionally, PLCβ3 has emerged as a potential target protein for treating allergic inflammation. In this study, we employed a virtual screening technique to search the Taiwan Traditional Chinese Medicine Database, followed by a second screening using absorption, distribution, metabolism, excretion, and toxicity (ADMET). Among the compounds screened, silibinin exhibited the best performance, forming strong hydrogen bond interactions with residues of PLCβ3, with a binding free energy of -119.277 kcal/mol. Therefore, silibinin effectively blocked the interaction between FcεRIβ and PLCβ3. Silibinin reduced the production of allergic inflammatory cytokines, including cytokine-induced neutrophil chemoattractant 2a (CINC-2a), interleukin-2 (IL-2), cytokine-induced neutrophil chemoattractant 1 (CINC-1), interleukin 1α (IL-1α), macrophage inflammatory protein 3 alpha (MIP3α), interferon γ (IFN-γ), activin A, granulocyte macrophage colony stimulating factor (GM-CSF), intercellular adhesion molecule-1 (ICAM-1), interleukin 4 (IL-4), interleukin 13 (IL-13), Fas ligand (FasL) and tumor necrosis factor alpha (TNF-α), without inducing cytotoxicity. Furthermore, in studies of IgE-mediated allergic responses, silibinin also decreased the expression of surface IgE receptors (FcεRIs). Moreover, silibinin effectively alleviated allergen-induced asthma responses and reduced the infiltration of inflammatory immune cells into the lungs of an OVA-induced allergic airway inflammation mouse model. Taken together, these results demonstrate the potential antiallergic mechanism of silibinin both in vitro and in vivo, making it a promising candidate for the development of asthma therapeutics.

Myocardial ischemia-reperfusion injury (MIRI) injury is a serious health problem, which can seriously affect the recovery of patients with myocardial infarction and even lead to death. Paeoniflorin (PF) is a potential therapeutic drug to prevent reperfusion injury. However, the mechanism of PF in MIRI is not clear. Compared with other cells, cardiomyocytes have the largest number of mitochondria. Therefore, this study researched the protective mechanism of paeoniflorin pretreatment on myocardial ischemia-reperfusion injury (AMI) from the perspective of mitochondrial autophagy. Paeoniflorin was given or not given to H9C2 cells 12 h before reperfusion. Pretreatment of paeoniflorin can significantly increase the viability of H9C2 cells and inhibit the increase of ROS secretion induced by OGD/R. The increase of MDC autophagy fluorescence and mitochondrial membrane potential (MMP) suggested that the myocardial protective effect of paeoniflorin may also be related to mitochondrial autophagy. Next, we detected the related signals in the classical mitochondrial autophagy pathway of PINK1/parkin by Q-PCR and Western blots. The results showed that the pretreatment of paeoniflorin could promote the levels of SIRT1, Beclin1, PINK1, parkin and LC3, inhibit the level of P62. In order to further clarify whether paeoniflorin-induced SIRT1 activation is necessary for autophagy and its potential mechanism, we detected the autophagy level of H9C2 cells with SIRT1 inhibitor (EX527). The results showed that after pretreatment of EX527, the protective effect of paeoniflorin on oxidative damage and autophagy pathway was significantly decreased. The mechanism may relate to SIRT1-PINK1/parkin mitochondrial autophagy pathway. In summary, these results suggested that paeoniflorin may protect H9C2 cells from OGD/R damage by activating SIRT1-PINK1/parkin pathway. This provides new experimental basis for paeoniflorin in the treatment of MIRI.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy. Programmed death ligand 1 of small extracellular vesicles (sEV-PDL1) induce immune evasion and enhance tumor progression. However, the role of ESCC derived sEV-PDL1 in modulating CD8T cell remains unclear. sEVs were isolated through differential centrifugation. CD8T cells were isolated, stimulated and cultured with sEVs to evaluate the proportions, phenotypes, and functions by flow cytometry. Lentivirus infection and Crisper-Cas9 were used to constructed stable transgenic cell lines: Eca109-PDL1 and mEC25-PDL1. The proportions of CD8T cells in ESCC patients was lower than healthy donors (HD). Furthermore, a negative correlation between sEV-PDL1 and CD8T cell was observed. sEV-PDL1 induced CD8T cell exhaustion by reducing the expression levels of Ki67, Granzyme B (GrzmB), and interferon-γ (IFN-γ) both in vitro and in vivo. However, anti-PDL1 reversed the result. Our findings reveal that targeting sEV-PDL1 to rejuvenate CD8T cell functions is one of the mechnisms a promising therapeutic strategy for ESCC.

Sepsis-induced myocardial dysfunction (SIMD) is a life-threatening complication primarily driven by inflammation, yet its molecular mechanisms remain unclear. In this study, we identified significant upregulation of the mA methyltransferase METTL3 (methyltransferase-like 3), the mA reader protein YTHDF1 (YTH N6-methyladenosine RNA binding protein 1), as well as increased expression levels of USP12 (ubiquitin-specific peptidase 12), FOXO3 (forkhead box O3), and key molecules in the intrinsic apoptotic pathway, PUMA (p53 upregulated modulator of apoptosis) and BAX (Bcl-2-associated X), through proteomic profiling in an LPS (Lipopolysaccharide)-induced SIMD mouse model. In vitro and in vivo experiments demonstrated that METTL3 and YTHDF1 regulated USP12 mRNA expression and stability through mA modification. Elevated USP12 interacted with FOXO3, preventing its ubiquitin-mediated degradation, which enhanced FOXO3 binding to the PUMA promoter, leading to upregulation of PUMA. PUMA upregulation initiated the intrinsic apoptotic pathway, activating downstream BAX, Apaf1 (apoptotic protease-activating factor 1), and Caspases, ultimately driving SIMD. Inhibition of METTL3 (with STM2457), YTHDF1 (with Ebselen), or PUMA (with CLZ-8) significantly suppressed intrinsic apoptosis and alleviated SIMD symptoms. These findings underscore the critical role of METTL3/YTHDF1-dependent mA modification in modulating the USP12-FOXO3-PUMA-BAX-Apaf1-Caspases signaling axis in SIMD, and suggest that targeting this pathway may offer a potential therapeutic strategy for SIMD.

The aim of this study was to reveal the mechanism of cold stimulation (CS)-bronchial epithelial cells (BECs) derived exosomes (CS-BECs-exo) aggravated sepsis induced acute lung injury (SALI). CS-BECs-exo were separated by differential centrifugation and were characterized. Proteomics, immunoprecipitation, and RAGE knockout (RAGE) mice were used to investigate the mechanism of CS-BECs-exo aggravated SALI. The results of transmission electron microscope (TEM) showed that CS-BECs-exo showed a double-layer membrane structure like a saucer. Nanoparticle tracking analysis (NTA) particle size analysis showed that the average particle size of CS-BECs-exo was 123.6 nm. The results of proteomics showed that the expression level HMGB1 was significantly increased in CS-BECs-exo compared with BECs-exo. CS-BECs-exo significantly increased oxidative stress and inflammatory reaction of SALI. In addition, CS-BECs-exo significantly increased RAGE and decreased the levels of Nrf-2 and OH-1. RAGE knockout (RAGE KO) and silence of RAGE (RAGE siRNA) significantly canceled the effects of CS-BECs-exo on SALI. HMGB1 knockout (HMGB1) and silence of HMGB1 also significantly (HMGB1 siRNA) canceled the effects of CS-BECs-exo on SALI. In conclusion, CS-BECs-exo aggravated ALI in sepsis via HMGB1/RAGE/Nrf-2/OH-1 signal pathway.

Gastric cancer mesenchymal stem cells (GC-MSCs) are a crucial component of the gastric cancer microenvironment, exerting a pivotal influence on the formation of a suppressive immune microenvironment and the progression of gastric cancer. In this study, we utilized GC-MSCs to co-culture peripheral blood mononuclear cells (PBMCs) obtained from both gastric cancer patients and healthy individuals in a proportionate manner by direct cell-to-cell contact. Our findings reveal that co-culture of GC-MSCs with PBMCs led to a notable reduction in CD8 T cells percentages and an increase in surface PD-1 expression levels on CD8 T cells. However, flow cytometry analysis demonstrated no significant changes following pretreatment with GC-MSC-conditioned medium (GC-MSC-CM). Moreover, western blotting analysis demonstrated a notable reduction in phosphorylated AKT levels in co-cultured PBMCs. Collectively, our results suggest that GC-MSCs impair the anti-tumor immune response of PBMCs by elevating the PD-1 levels of CD8 T cells and impairing the killing of CD8 T cells. These findings provide new evidence that GC-MSCs contribute to immunosuppression within the tumor microenvironment (TME).

Acute lung injury (ALI) ranks among the leading reasons for death in septic patients. As an essential transcription factor associated with stress, activating transcription factor 3 (ATF3) participates in a variety of pathophysiological processes, including immunology and inflammation. However, the specific mechanism of ATF3 in pyroptosis of sepsis-induced ALI remains elusive.

Phosphoribosylformylglycinamidine synthase (PFAS) is a critical enzyme in de novo synthesis of purine. Innate immunity recognizes tumor derived damage-associated molecular patterns (DAMPs) and initiates the anti-tumor adaptive responses. While the function of PFAS catalyzed de novo synthesis of purine is well proved, its effect on innate immune evasion in cancer is unclear and needs to be further explored. The purpose of this study was to investigate the specific mechanisms by which PFAS inhibits RIG-I receptor (RLR) -mediated NF-κB axis in CRC.

The spleen is an important immune organ in adult Xenopus laevis, supporting the differentiation of B cells and acting as the main peripheral lymphoid organ. Key to these processes are the supporting non-hematopoietic cells, or stromal cells, within the spleen tissue. Despite the importance of the spleen to frog immunity, few frog cell lines originating from spleen tissue have been reported. In this study, we report on the establishment and characterization of two cell lines originating from X. laevis spleen tissue, Xela S5F and Xela S5E. Morphological observations and gene expression profiling suggest that Xela S5F is fibroblast-like and Xela S5E is epithelial-like. Both cell lines express transcripts corresponding to a variety of hematopoietic growth factors, suggesting their potential utility as a feeder cell line to support ex vivo myelopoietic cell differentiation. Xela S5F and Xela S5E produce transcripts for a diversity of pattern recognition receptors including toll-like receptors, scavenger receptors, and cytosolic nucleic acid sensors, suggesting anuran spleen stromal cells may be important cellular sensors of pathogens filtered through the spleen. This idea is supported by the increase in transcript levels for antiviral and proinflammatory genes in both cell lines in response to treatment with the commercially available toll-like receptor ligands, flagellin and poly(I:C). However, despite the ability to sense extracellular synthetic analogues of viral nucleic acids [i.e. poly(I:C)] and susceptibility and permissibility of both cell lines to frog virus 3 (FV3), a large double-stranded DNA virus that infects amphibians, neither cell line upregulates key antiviral or proinflammatory transcripts when challenged with FV3. The establishment of Xela S5F and S5E cell lines expands the current X. laevis invitrome and provides new in vitro cell model systems to investigate the role of splenic stromal cells in anuran immune functions.