Jinjuan Wen,1,* Sihao Hong,2,* Jiaman Lai,3 Keyun Chen,3 Lingli Li,3 Shaoru Jiang1,31Reproductive Medicine Center, Jieyang People’s Hospital, Jieyang Cancer Center, Jieyang, Guangdong, People’s Republic of China; 2Department of Urology, Jieyang People’s Hospital, Jieyang Cancer Center, Jieyang, Guangdong, People’s Republic of China; 3Department of Obstetrics and Gynecology, Jieyang People’s Hospital, Jieyang Cancer Center, Jieyang, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaoru Jiang, Email jshaoru@gdmu.edu.cnBackground: Sepsis represents a severe challenge in critical‑care medicine. Protecting endothelial function and alleviating microvascular inflammation and oxidative stress help reduce sepsis‑associated mortality. Apigenin, a natural flavonoid, exerts anti‑inflammatory and anti‑oxidant effects; its mechanisms against endothelial injury relevant to sepsis remain unclear.Purpose: This study combined computational biology and in‑vitro assays to explore potential targets of apigenin against lipopolysaccharide‑triggered endothelial dysfunction.Methods: Network pharmacology was performed for target screening followed by GO and KEGG enrichment. Transcriptomic profiles were analyzed. Molecular docking and 100‑ns molecular dynamics simulations predicted apigenin‑protein interactions. An LPS‑stimulated HUVECs injury model was established. qRT-PCR, ELISA, flow cytometry and fluorescent probes were used to evaluate inflammation, apoptosis, reactive oxygen species and monocyte adhesion.Results: A total of 104 intersecting targets were identified. AKT1, HSP90AA1, EGFR, ESR1 and HIF1A were potential core candidates, with PI3K‑Akt, TNF and HIF‑1 signaling possibly involved. Simulations predicted relatively stable apigenin‑protein complexes. At 40 μM, apigenin mitigated LPS‑provoked inflammatory response, oxidative stress, apoptosis and monocyte adhesion in HUVECs.Conclusion: Apigenin protects HUVECs from LPS‑induced endothelial injury possibly via multi‑target and multi‑pathway patterns. This study provides preliminary computational and in vitro evidence for further investigation of apigenin against LPS-triggered endothelial injury, with potential implications for sepsis-associated vascular damage that requires further in vivo validation.Keywords: apigenin, sepsis, endothelial dysfunction, inflammation, network pharmacology, molecular dynamics simulation
Wiqar Adnan Azeez Aboomaima,1 Abbas Hasan Burhan,2 Hiba Adnan Aziz Abu Omaima,2 Ali Mahmoudi31College of Science, Al-Qadisiya University, Al-Diwaniya, Iraq; 2College of Biotechnology, Al-Qadisiya University, Al-Diwaniya, Iraq; 3Department of Basic Medical Sciences, Faculty of Medicine, Abadan University of Medical Sciences, Abadan, IranCorrespondence: Ali Mahmoudi, Department of Basic Medical Sciences, Faculty of Medicine, Abadan University of Medical Sciences, Abadan, Iran, Tel +98 9169370231, Email Alimahmoudi68@yahoo.comAbstract: Nitric oxide (NO), produced by nitric oxide synthase (NOS) isoforms, plays a dual role in the central nervous system. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has shown promise as a neuroprotective and anti-inflammatory agent. This narrative review examines the complex interactions between CBD and NOS isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) variants, and discusses how these may contribute to its neuroprotective and analgesic properties. Preclinical evidence, primarily from cellular and animal models, indicates that CBD can reduce excessive NO production, particularly by inhibiting iNOS in neuroinflammatory conditions. However, the effects of CBD on nNOS are context-dependent and cannot be characterized simply as inhibitory: while CBD may attenuate pathological nNOS-mediated excitotoxicity in some models, nNOS-derived NO is also required for CBD-induced analgesia in certain neuropathic pain models, where nNOS activation and downstream NO signaling contribute to antinociception. The strongest preclinical evidence supports CBD-mediated suppression of pathological iNOS expression and NO production in neuroinflammatory conditions. The effects of CBD on nNOS are context-dependent and cannot be characterized simply as inhibitory: while CBD may attenuate pathological nNOS-mediated excitotoxicity in some models, nNOS-derived NO is also required for CBD-induced analgesia in certain neuropathic pain models, where nNOS activation and downstream NO signaling contribute to antinociception. Similarly, evidence for eNOS-mediated vascular benefits in the CNS remains preliminary and largely derived from peripheral studies, and cerebrovascular eNOS effects require further investigation. We review the potential therapeutic implications of these interactions in neurological conditions such as Alzheimer’s disease, multiple sclerosis, depression, and neuropathic pain. The review also addresses antioxidant and anti-nitrosative benefits of CBD, pharmacokinetic challenges, and research gaps, including the need for clinical trials with biomarkers to validate NOS-related findings. By integrating molecular, preclinical, and translational perspectives, this review provides insights into the context-dependent and isoform-selective modulation of NOS by CBD, emphasizing that the strength of evidence varies by isoform, with iNOS and nNOS modulation being better established than eNOS-related effects.Keywords: cannabidiol, nitric oxide synthase, neurodegeneration, neuropathic pain, blood–brain barrier
XiaoXin Wang,1,* Min Ling,2,* FuJun Liu11Shandong Stem Cell Engineering Technology Research Center, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, People’s Republic of China; 2The First Clinical School of Medicine, Zhengzhou University, Zhengzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: FuJun Liu, Email sdstemcell@126.comAbstract: The CKLF-like MARVEL transmembrane domain-containing (CMTM) family has emerged as a functionally diverse group of membrane-associated regulators involved in receptor stability, vesicular trafficking, and immune homeostasis. Increasing evidence suggests that selected CMTM proteins influence macrophage biology in a context-dependent manner, particularly under conditions of tumor-associated immune suppression, systemic inflammatory stress, and innate immune overactivation. Among the family members implicated to date, CMTM6 is the best-established regulator of programmed death-ligand 1 (PD-L1) stability and thereby contributes to immune evasion in cancer, with emerging evidence suggesting additional effects on macrophage immunoregulatory programming in selected tumor settings. CMTM4 shares partially overlapping activity in PD-L1 regulation, but its macrophage-specific role, especially in sepsis-associated immune dysfunction, remains incompletely defined. In contrast, CMTM7 has been identified as a candidate endogenous negative regulator of macrophage inflammatory activation, functioning through trafficking-dependent control of Toll-like receptor 4 (TLR4) signaling and signal termination. Collectively, current data support a model in which CMTM proteins modulate macrophage responses through membrane-proximal mechanisms governing checkpoint expression, receptor trafficking, inflammatory amplitude, and possibly cell survival. In this review, we summarize current evidence connecting CMTM proteins to macrophage inflammation response in cancer, sepsis, and other inflammatory disease, distinguish established mechanisms from emerging hypotheses, discuss major methodological limitations, and outline priorities for future mechanistic and translational studies.Keywords: CMTM, macrophage, inflammation, sepsis, tumor microenvironment, receptor trafficking
Pai Peng,1,2 Peng Zhou,3 Zitao Liu,4 Haoyuan Shen,2 Chaohua Hu,2 Jun Jiang11Department of Thyroid Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2Department of Breast and Thyroid Surgery, The Central Hospital of Xiaogan & Xiaogan Hospital Affiliated to Wuhan University of Science and Technology, Xiaogan, Hubei, 432100, People’s Republic of China; 3Department of General Surgery (Breast Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 4School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People’s Republic of ChinaCorrespondence: Jun Jiang, Department of Thyroid Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, 646000, People’s Republic of China, Email jiangjun@swmu.edu.cnBackground: CD97 is overexpressed in various cancers, but its function and immunoregulatory role in triple-negative breast cancer (TNBC) remain unclear. This study aimed to investigate the expression, function, and potential regulatory mechanisms of CD97 in TNBC.Methods: CD97 expression, clinical associations, and immune infiltration were evaluated using TCGA, KM Plotter, and GEO bulk, single-cell, and spatial transcriptomic datasets. THP-1-derived M1a/M1b macrophage models with CD97 knockdown or overexpression were used to assess phagocytosis, cytokine secretion, and effects on tumor and endothelial cells. Zinc modulation, NF-κB inhibition, Western blotting, pseudotime analysis, transcription-factor screening, and network analyses were used to explore potential mechanisms.Results: CD97 was upregulated in TNBC and enriched in M1 macrophages. In a pooled KM Plotter analysis, high CD97 expression was associated with favorable relapse-free survival; however, CD97 was not significantly associated with overall survival in the TCGA-TNBC cohort in univariable or stage-adjusted Firth Cox analyses. In M1a macrophages, CD97 perturbation altered phagocytic activity, tumor-cell apoptosis, intracellular zinc homeostasis, and NF-κB signaling, with pharmacological inhibition supporting NF-κB as a downstream mediator. In M1b macrophages, CD97 knockdown increased, whereas overexpression decreased, MDA-MB-231 migration and invasion in vitro. SPI1 perturbation altered CD97 expression, supporting SPI1 as a potential upstream regulator rather than establishing direct transcriptional control.Conclusion: CD97 is associated with immune-active features in TNBC and modulates macrophage functions in vitro. Its prognostic relevance appears context- and dataset-dependent, and further in vivo and clinical validation is required before translational application.Keywords: CD97, triple-negative breast cancer, M1 macrophages, tumor immune microenvironment, mechanisms
Jin Li,1,* Yaxian Luo,2,* Jinyi Ma,1,* Shuangyang Li,2 Mouyuan Sun21Department of Ophthalmology, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, People’s Republic of China; 2Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mouyuan Sun, Email sunmouyuan777@zju.edu.cnBackground: Diabetes is a multifactorial chronic metabolic disorder in which chronic low-grade inflammation contributes to the initiation and progression of type 2 diabetes mellitus (T2DM). Investigations of the diabetes-inflammation axis have remained persistently compartmentalized, compelling a systematic synthesis of macroscale bibliometric trajectories with microscale microenvironmental circuitry.Purpose: This study integrates a 20-year bibliometric analysis with single-cell transcriptomic analysis to characterize the research landscape and examine inflammatory activity at cellular resolution.Methods: A corpus of 55,147 English‑language publications spanning 2006– 2026 was curated from the Web of Science Core Collection (WoSCC). CiteSpace, Bibliometrix, and Tableau were harnessed to perform collaboration network mapping, co‑citation dissection, and thematic evolution tracing. In parallel, single-cell RNA sequencing data from two T2DM and two control peripheral blood mononuclear cell samples (GSE280401) were analyzed; after quality control, 2,611 T2DM cells and 4,138 control cells were retained, AUCell was used to quantify inflammatory pathway activity, and CellChat was used to infer intercellular immune communication.Results: Macroscopically, the field has witnessed exponential publication acceleration, with China and the United States constituting the dominant research poles and U.S. institutions commanding disproportionate network centrality. The thematic epicenter has undergone a decisive migration from classical inflammatory cytokine postulates toward immunometabolic network orchestration and multi‑target therapeutic frameworks, while cardiovascular protection, oxidative stress, and molecular docking have crystallized as the defining frontier. At the single-cell level, T cells were the most abundant population, overall inflammatory-response scores were higher in T2DM cells, and CellChat suggested reduced global communication with relative enrichment of several pro-inflammatory pathways.Conclusion: By erecting a macro-micro dual‑scale knowledge architecture, this study renders visible the foundational intellectual scaffolding and evolutionary trajectory of the diabetes-inflammation axis. The findings identify testable priorities in immunometabolic regulation and ligand-receptor signaling that require confirmation in larger cohorts and functional studies.Keywords: diabetes mellitus, inflammation, bibliometrics, single-cell analysis, precision therapy
