Qixiang Shao

Sepsis is a life-threatening syndrome of multi-organ dysfunction caused by a dysregulated host response to infection. Despite advances in supportive care, the underlying immunopathological mechanisms remain incompletely understood. A hallmark of sepsis is immunoparalysis, characterized by an early hyperinflammatory phase followed by sustained immunosuppression, predisposing patients to secondary infections and adverse outcomes. A central feature of this process is profound lymphopenia accompanied by impaired T-cell effector function. This review synthesizes current evidence on T-cell perturbations during sepsis, encompassing numerical depletion, persistent upregulation of inhibitory immune checkpoints, and dysregulated cytokine signaling. We further highlight emerging evidence on four major modes of T-cell loss and dysfunction: apoptosis, autophagy dysfunction, pyroptosis, and ferroptosis, and discuss their integrated impact on immune competence. A deeper understanding of the mechanisms underlying T-cell death may facilitate the development of targeted immunomodulatory strategies and adjunctive therapies for sepsis, an area where effective interventions remain limited.

Objective: Sonic Hedgehog (Shh)-Gli1 signaling and osteopontin ( OPN ) play vital roles in pancreatic cancer. However, the precise mechanisms of both signals have not been fully clarified, and whether there is a correlation between them in pancreatic ductal adenocarcinoma (PDAC) is unknown. This study aims to confirm the effect of OPN on human PDAC and assess whether Hh signaling affects pancreatic cancer cells through upregulation of OPN . Materials and Methods: OPN expression in human PDAC tissues and cell lines was investigated. Proliferation, apoptosis, migration, and invasion of OPN -knockdown BxPC-3 cells were observed. We analyzed the correlation between Shh or Gli1 and OPN expression in human PDAC. Hh signaling inhibitors and shRNA against Gli1 were used to confirm if OPN expression in BxPC-3 cells was regulated by Hh canonical or noncanonical pathway. We also evaluated the proliferation, apoptosis, migration, and invasion of Gli1 -knockdown BxPC-3 cells. Results: OPN is highly expressed in human PDAC tissues and cell lines. The proliferation, migration, and invasion of BxPC-3 cell lines were decreased, whereas apoptosis was increased when OPN was knocked down. Correlation analysis showed that Gli1 , but not Shh , was associated with OPN expression in human PDAC, and Gli1 regulated OPN production in BxPC-3 cells through a noncanonical pathway because Gli but not Smo inhibitor reduced OPN expression. Similar to above, the proliferation, migration, and invasion of BxPC-3 cells were decreased, whereas the apoptosis was increased when Gli1 was knocked down. Supplement of exogenous OPN protein could partially reverse the effect of both OPN knockdown and Gli1 knockdown on the bio-behavior of BxPC-3 cells. Conclusion: Hh signaling promotes proliferation, migration, and invasion but inhibits apoptosis of pancreatic cancer cells through upregulation of OPN in a noncanonical pathway.

Graft-versus-host disease (GVHD) remains the most severe complications following allogeneic hematopoietic cell transplantation (allo-HCT). Mesenchymal stromal cells (MSCs) have shown therapeutic potential in GVHD due to their immunomodulatory properties. However, their clinical application is constrained by safety concerns, including ectopic engraftment, microvascular obstruction, rejected by host, and potential tumor-supportive effects. Increasing evidence suggests that MSC-derived exosomes (MSC-Exos), as cell-free mediators, retain many of the beneficial effects of MSCs while exhibiting improved safety and stability profiles. MSC-Exos carry diverse bioactive cargo, including nucleic acids, lipids, and proteins, and can modulate immune responses, promote tissue repair, and restore barrier integrity. In this review, we place particular emphasis on both immunoregulation and tissue barrier protection as dual mechanisms underlying MSC-Exos efficacy in GVHD. We further discuss emerging preclinical and clinical evidence, as well as key challenges in translation.

Breast cancer (BC) heterogeneity, particularly in triple-negative (TNBC) and HER2-positive subtypes, underpins therapeutic challenges and cancer-related mortality worldwide. Here, we identify the transmembrane oxidoreductase CYB561 as a pivotal oncoprotein that drives BC malignancy by coordinating lipid metabolic reprogramming and oncogenic signaling. CYB561 was significantly overexpressed in BC tissues, especially in HER2-positive (70%) and TNBC (60%) cases, and its expression correlated with advanced T stage, metastasis, and poor patient survival. Functionally, CYB561 potently promoted proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and tumor growth in vitro and in vivo. Mechanistically, CYB561 directly bound IRE1, triggering the IRE1–XBP1–SREBF1 axis to induce lipogenic enzyme expression and lipid droplet accumulation. Concurrently, it activated the FAK–ERK signaling pathway. Crucially, IRE1 knockdown abolished CYB561-induced lipogenesis and malignant phenotypes, while ERK inhibition partially attenuated these effects, revealing a synergistic crosstalk between metabolic and signaling axes. Our findings establish CYB561 as a master regulator of BC progression and nominate it as a promising therapeutic target for aggressive breast cancers.

Background: Perimenopausal women often experience physiological and psychological decline due to the effects of oestrogen fluctuations and the decline of ovarian function, leading to significantly increased depression rates, decreases in the quality of life and mental health issues. Studies have shown that the gut microbiota exerts anti-perimenopausal depression (PMD) effects via the microbiota-gut-brain (MGB) axis, the mechanisms of which may be related to inflammation. In this review, we discuss the effects and mechanisms of gut microbiota in PMD and provide new insights for future PMD treatment. Methods: This review elaborates on the role of MGB axis in PMD from different aspects of inflammation, including gut microbiota metabolites, inflammatory signaling pathways, and clinical applications. Results: Disorders of gut microbiota and decreased levels of gut microbiota metabolites (short-chain fatty acids, monoamine neurotransmitters) may cause PMD. The mechanism of intestinal microbiota-mediated inflammation may be related to TLR4/NF-κB pathway, NOD-like receptor protein 3 (NLRP3) inflammasome pathway and JAK-STAT pathway. At the same time, it was found that gut microbiota (probiotics, prebiotics, etc.) had good therapeutic potential in the treatment of PMD. Conclusions: MGB axis mediated inflammation may play an important role in PMD. The application of gut microbiota in the treatment of PMD patients has profound clinical transformation value, but a lot of efforts are still needed.

The Wnt signaling pathway is broadly categorized into two major classes: Canonical and non‑canonical pathways. The canonical Wnt pathway, which is also referred to as the Wnt/β‑catenin pathway, involves the nuclear translocation of β‑catenin. By contrast, non‑canonical Wnt pathways, including the Wnt/Ca²⁺ pathway and the Wnt/planar cell polarity pathway, function independently of β‑catenin nuclear translocation. Among these non‑canonical pathways, the Wnt/Ca²⁺ pathway influences cellular behavior by elevating intracellular Ca²⁺ concentrations. This pathway primarily regulates cytoskeletal remodeling, cell migration, polarity and immune responses, and serves a crucial role in cell proliferation, differentiation, embryonic development and tumorigenesis. Notably, Wnt/Ca²⁺ signaling exhibits dual functions in different tumor types, promoting tumorigenesis in certain cancers, whilst inhibiting it in others. The present review systematically summarizes research regarding the Wnt/Ca²⁺ signaling pathway, elucidates its mechanisms in cancer progression, and outlines current strategies for targeting the Wnt/Ca²⁺ signaling pathway in cancer, along with the associated challenges.

Hyperinflammatory response in early stage of sepsis was the key factor leading to multi-organ injury. Therefore, exploring an effective therapy to attenuate or reverse hyperinflammation was the priority of sepsis treatment. Previous study from our team showed that recombinant human interleukin-11 (rhIL-11) was a promising anti-inflammation cytokine in sepsis. However, the molecular mechanism was not fully elucidated. This study aims to evaluate the therapeutic potential of rhIL-11 in septic mice model and explore the underlying the molecular mechanism. A cecal ligation and puncture (CLP) model was applied to induce septic mice. Mice were separated into five groups with six animals in each group, including normal, sham, sham + rhIL-11, CLP and CLP + rhIL-11 groups. Therapeutic potential of rhIL-11 was evaluated by comparing body weight, survival time and liver damage (hematoxylin and eosin (H&E) staining, pro-inflammatory cytokines and serum measurements of liver enzymes). Hepatic myeloid-derived suppressor cells (MDSC) percentage was also compared. In vitro, MDSC differentiation from bone marrow (BM) cells was induced in the presence of appropriate stimuli, followed by the proportion and subsets analysis via flow cytometer. The related signal pathways including STAT3 and mTORC1 were detected by western blotting. The effect of MDSCs inhibition by STAT3 and mTORC1 inhibitors on septic mice was evaluated by comparing survival time, liver damage and MDSCs percentage. Here, we declared that early treatment of rhIL-11 exerted a liver protective effect and caused the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) in septic mice model. The results of in vitro studies declared that rhIL-11 promoted differentiation of BM cells into M-MDSCs phenotypically and functionally via activating STAT3 signaling, which was cross-regulated by the mTORC1. Furthermore, we also elucidated that mTORC1 bound directly to STAT3 through an interaction between raptor and TOS motif in STAT3. Finally, inhibition of mTORC1 or STAT3 in vivo blocked the differentiation of M-MDSCs and attenuated liver protective effect of rhIL-11. Taken together, these results suggested that early treatment of rhIL-11 in septic mice might reverse the hepatic damage at least in part by inducing the differentiation of M-MDSCs via STAT3 signaling pathway, and STAT3 signaling is modulated by a parallel branch of mTORC1.

As the population aging, the prevalence of age-related diseases is also rising. Mitochondrial malfunction is one of the hallmarks of aging, and optic atrophy type 1 (OPA1), a protein found in the inner membrane (IM) of mitochondrial, is essential to this process. OPA1 regulates the fusion of IM and cristae structure, hence maintaining cellular energy metabolism and function. Its abnormalities may impair the multiple functions of tissues and are also closely related to various diseases. OPA1 is highly expressed in metabolically active organs, such as the brain, skeletal muscle, and heart, ensuring the normal metabolism and function of these organs. This review summarizes the physiological functions of OPA1 in these organs, along with the effect of aberrant OPA1 expression on aging related disorders. By deeply studying the mechanisms of OPA1’s function in these diseases, we might achieve a more profound comprehension of the pathological processes of age-related diseases and explore potential therapeutic strategies.

The capacity of lymphocytes continuously home to lymphoid structures is remarkable for cancer immunosurveillance and immunotherapy. Lymphocyte homing and recirculation within the tumor microenvironment (TME) are now understood to be adaptive processes that are regulated by specialized cytokines and adhesion molecule signaling cascades. Restricted lymphocyte infiltration and recirculation have emerged as key mechanisms contributing to poor responses in cancer immunotherapies like chimeric antigen receptor (CAR)-T cell therapy and immune checkpoint blockades (ICBs). Uncovering the kinetics of lymphocytes in tumor infiltration and circulation is crucial for improving immunotherapies. In this review, we discuss the current insights into the adhesive and migrative molecules involved in lymphocyte homing and transmigration. The potential mechanisms within the TME that restrain lymphocyte infiltration are also summarized. Advanced on these, we outline the determinates for tertiary lymphoid structures (TLSs) formation within tumors, placing high expectations on the prognostic values of TLSs as therapeutic targets in malignancies.

Alterations in glycosylation are associated with breast tumor formation and progression. Nevertheless, the specific functions and mechanisms of the human major UDP‐galactose transporter‐encoding gene solute carrier family 35 member A2 (SLC35A2) in breast invasive carcinoma (BRCA) have not been fully determined. Here, we report that SLC35A2 promotes BRCA progression by activating extracellular signal regulated kinase (ERK). SLC35A2 expression and prognosis‐predictive significance in pan‐cancer were evaluated using public databases. The upstream non‐coding RNAs (ncRNAs) of SLC35A2 were analyzed, and their expression and regulations were validated in breast tissues and cell lines by a quantitative PCR and dual‐luciferase assays. We used bioinformatic tools to assess the link between SLC35A2 expression and immune infiltration and performed immunohistochemistry for validation. Cell Counting Kit‐8, 5‐ethynyl‐2′‐deoxyuridine, transwell, flow cytometer and western blotting were used to assess the proliferation, motility, cell cycle and apoptosis of BRCA cells in vitro. The xenograft models were constructed to assess the effect of SLC35A2 on BRCA tumor growth in vivo. The results indicated that SLC35A2 expression was upregulated and linked to an unfavorable prognosis in BRCA. The most likely upstream ncRNA‐associated pathway of SLC35A2 in BRCA was the AC074117.1/hsa‐let‐7b‐5p axis. SLC35A2 expression had positive correlations with the presence of Th2 cells, regulatory T cells and immune checkpoints. Knockdown of SLC35A2 could reduce BRCA cell proliferation, motility, and cause G2/M arrest and cell apoptosis via ERK signaling. Moreover, ERK activation can rescue the inhibitory effects of knockdown SLC35A2 in BRCA. In conclusion, AC074117.1/hsa‐let‐7b‐5p axis‐mediated high expression of SLC35A2 acts as a tumor promoter in BRCA via ERK signaling, which provides a potential target for BRCA treatment.