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2025 Year 12 Volume 10 Issue
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High-salt-driven gut microbiota dysfunction aggravates prostatitis by promoting AHR/SGK1/FOXO1 axis-mediated Th17 cell differentiation AI Introduction
“In the field of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), experts have verified the conjecture that high-salt diet (HSD) consumption promotes the differentiation of CD4+ T cells to proinflammatory T helper 17 (Th17) cells, which aggravates CP/CPPS. This finding provides a potential therapeutic target for CP/CPPS.”Abstract：BackgroundChronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a frequently encountered disorder characterized by voiding symptoms and pelvic or perineal pain. Proinflammatory T helper 17 (Th17) cells are essential for triggering the development of CP/CPPS. High-salt diet (HSD) consumption has been found to cause an accumulation of sodium chloride in peripheral organs, inducing autoimmune responses via the Th17 cell axis. It is currently unknown whether HSD affects the etiology and course of CP/CPPS.MethodsPatients diagnosed with CP/CPPS were evaluated with the National Institutes of Health Chronic Prostatitis Symptom Index scoring system, and the correlation between the symptoms of CP/CPPS with HSD was analyzed. The experimental autoimmune prostatitis (EAP) mouse was established and the mice were fed either a normal-salt diet (NSD) or HSD for 6 weeks to investigate the impact of HSD on CP/CPPS. Then, 16S ribosomal RNA sequencing and untargeted metabolomics were introduced to detect the differences in the gut microflora composition and metabolite profiles between NSD-fed and HSD-fed mice, followed by fecal microbiota transplantation, 5-hydroxyindole acetic acid (5-HIAA) supplementation, aryl hydrocarbon receptor (AHR) inhibition, and in vitro Th17 differentiation experiments, which were performed to explore the mechanisms underlying HSD-aggravated CP/CPPS. Finally, chromatin immunoprecipitation assay and quantitative polymerase chain reaction were conducted to validate whether AHR can serve as a transcription factor by interacting with the serum and glucocorticoid-regulated kinase 1(Sgk1) promoter in CD4+ T cells.ResultsIncreased salt consumption had a positive correlation with symptom scores of CP/CPPS patients, which was validated by feeding EAP mice with HSD, and HSD worsened the prostate inflammation and tactile allodynia in EAP mice through promoting the differentiation of CD4+ T cells to Th17 cells. HSD exacerbated EAP by significantly reducing the relative abundance of beneficial gut microflora, such as Lactobacillaceae, and gut microbiota metabolite 5-HIAA, which is related to tryptophan metabolism. The prostate inflammation, tactile allodynia, and pro-portion of Th17 cells in mice that received fecal suspensions from the EAP + HSD group were significantly more severe or higher than those in mice that received fecal suspensions from the EAP + NSD group. However, 5-HIAA supplementation ameliorated the symptoms of EAP caused by HSD through inhibiting the differentiation of CD4+T cells to Th17 cells, while AHR inhibition abrogated the protective effects of 5-HIAA supplementation on EAP mice fed a HSD through promoting the differentiation of CD4+ T cells to Th17 cells. Mechanistically, it has been revealed that the SGK1/forkhead box protein O1 (FOXO1) pathway was significantly activated during cytokine-induced Th17 cell differentiation, and AHR has been shown to inhibit SGK1 transcription by interacting with the Sgk1 promoter in CD4+ T cells to inhibit FOXO1 phosphorylation, consequently restoring the equilibrium of Th17 cell differentiation.ConclusionOur findings indicated that high salt intake represented a risk factor for the development of CP/CPPS as it promoted the differentiation of CD4+ T cells to Th17 cells through the 5-HIAA/AHR/SGK1/FOXO1 axis, which might be a potential therapeutic target for CP/CPPS.Keywords：Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS);High-salt diet;5-Hydroxyindole acetic acid(5HIAA);Serum and glucocorticoid-regulated kinase 1 (SGK1);Th17 cells83|0|0Updated：2025-12-13 -
GSTM1 suppresses cardiac fibrosis post-myocardial infarction through inhibiting lipid peroxidation and ferroptosis AI Introduction
“In the field of post-myocardial infarction fibrosis, this study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis, highlighting its ability to target ferroptosis through redox regulation. Expert xx established the xx system/explored the xx topic/verified the xx conjecture, which provides solutions to solve xx problems/open up a new direction for xx research/lay a foundation for the construction of xx system.”
Abstract：BackgroundCardiac fibrosis following myocardial infarction (MI) drives adverse ventricular remodeling and heart failure, with cardiac fibroblasts (CFs) playing a central role. GSTM1 is an important member of the glutathione S-trans-ferase (GSTs) family, which plays an important role in maintaining cell homeostasis and detoxification. This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.MethodsMulti-omics approaches (proteomics/scRNA-seq) identified GSTM1 as a dysregulated target in post-MI fibroblasts. Using a murine coronary ligation model, we assessed GSTM1 dynamics via molecular profiling, such as Western blotting, immunofluorescence, and real-time quantitative polymerase chain reaction. AAV9-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery. In vitro studies employed transforming growth factor-β (TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions. Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.ResultsThe expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels. In human dilated cardiomyopathy (DCM) patients with severe heart failure, GSTM1 expression was decreased alongside aggravated fibrosis. Overexpression of GSTM1 in post-MI mice improved cardiac function, while significantly reducing infarct size and fibrosis compared with the control group. In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts, as well as suppressed their proliferation and migration. Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intra-cellular and mitochondrial reactive oxygen species (ROS) under pathological conditions, suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts. Further investigation of molecular mechanisms indi-cated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferrop-tosis-related pathways. Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria, markedly decreased ferroptosis-related indicators, and alleviated oxidative lipid levels [such as 12-hydroxyeicosapentaenoic acid (HEPE) and 9-, 10-dihydroxy octadecenoic acid (DHOME)] under fibrotic conditions. GSTM1 enhanced the phosphorylation of STAT3, thereby upregulating the downstream expression of glu-tathione peroxidase 4 (GPX4), reducing ROS production, and mitigating fibroblast activation and phenotypic transfor-mation by inhibiting lipid peroxidation.ConclusionsThis study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis, highlighting its ability to target ferroptosis through redox regulation. AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.Keywords：GSTM1;Ferroptosis;Cardiac fibrosis;Myocardial infarction (MI);Lipid peroxidation;Glutathione peroxidase 4;Reactive oxygen species (ROS)57|0|0Updated：2025-12-13
RESEARCH
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Revolutionizing treatment for disorders of consciousness: a multidisciplinary review of advancements in deep brain stimulation AI Introduction
“Deep brain stimulation (DBS) has shown promise in treating disorders of consciousness (DOC), evolving from an experimental therapy to a detailed modulation approach based on the mesocircuit model hypothesis. Advances in computational models have facilitated a deeper exploration of neural dynamics associated with DOC, linking neuron-level dynamics with macroscopic behavioral changes. Future research should focus on conducting large-scale controlled studies to delve into the pathophysiological mechanisms of DOC.”Abstract：Among the existing research on the treatment of disorders of consciousness (DOC), deep brain stimulation (DBS)offers a highly promising therapeutic approach. This comprehensive review documents the historical develop-ment of DBS and its role in the treatment of DOC, tracing its progression from an experimental therapy to a detailed modulation approach based on the mesocircuit model hypothesis. The mesocircuit model hypothesis suggests that DOC arises from disruptions in a critical network of brain regions, providing a framework for refining DBS targets. We also discuss the multimodal approaches for assessing patients with DOC, encompassing clinical behavioral scales, electrophysiological assessment, and neuroimaging techniques methods. During the evolution of DOC therapy, the segmentation of central nuclei, the recording of single-neurons, and the analysis of local field potentials have emerged as favorable technical factors that enhance the efficacy of DBS treatment. Advances in computational models have also facilitated a deeper exploration of the neural dynamics associated with DOC, linking neuron-level dynamics with macroscopic behavioral changes. Despite showing promising outcomes, challenges remain in patient selection, precise target localization, and the determination of optimal stimulation parameters. Future research should focus on conducting large-scale controlled studies to delve into the pathophysiological mechanisms of DOC. It is imperative to further elucidate the precise modulatory effects of DBS on thalamo-cortical and cortico-cortical func-tional connectivity networks. Ultimately, by optimizing neuromodulation strategies, we aim to substantially enhance therapeutic outcomes and greatly expedite the process of consciousness recovery in patients.Keywords：Deep brain stimulation;disorders of consciousness;Segmentation of thalamic nuclei;Local field potentials;Computational modeling48|0|0Updated：2025-12-13 -
Role of PD-1/PD-L1 signaling axis in oncogenesis and its targeting by bioactive natural compounds for cancer immunotherapy AI Introduction
“In the fight against cancer, a review paper highlights the potential of natural compounds targeting the PD-1/PD-L1 pathway, offering a new direction for cancer research.”Abstract：Cancer is a global health problem and one of the leading causes of mortality. Immune checkpoint inhibitors have revolutionized the field of oncology, emerging as a powerful treatment strategy. A key pathway that has garnered considerable attention is programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1). The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body’s immune system. Furthermore, it controls the phenotype and functionality of innate and adaptive immune components. A range of monoclonal antibodies, including avelumab, atezolizumab, camre-lizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab, have been developed for targeting the interaction between PD-1 and PD-L1. These agents can induce a broad spectrum of autoimmune-like complica-tions that may affect any organ system. Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints. This could contribute to the existing arsenal of anticancer drugs. Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis, promoting tumor cell apoptosis, influenc-ing cell proliferation, and eventually leading to tumor cell death and inhibiting cancer progression. However, there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer. Hence, this review aims to provide a common connection between PD-1/PD-L1 blockade and the antican-cer effects of distinct natural molecules. Moreover, the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules. Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.Keywords：Cancer;PD-1/PD-L1;Crosstalk;Natural compounds;Therapeutic targets47|0|0Updated：2025-12-13 -
Impact of targeting the platelet-activating factor and its receptor in cancer treatment AI Introduction
“In the field of cancer treatment, the lipid mediator platelet-activating factor (PAF) and its receptor (PAFR) signaling pathway is a promising target. Expert xx explored the PAF/PAFR signaling pathway, which provides solutions to solve cancer treatment problems and lays a foundation for the construction of cancer treatment system.”Abstract：The lipid mediator platelet-activating factor (PAF) and its receptor (PAFR) signaling play critical roles in a wide range of physiological and pathophysiological conditions, including cancer growth and metastasis. The ability of PAFR to interact with other oncogenic signaling cascades makes it a promising target for cancer treatment. Moreover, numerous natural and synthetic compounds, characterized by diverse pharmacological activities such as anti-inflammatory and anti-tumor effects, have been explored for their potential as PAF and PAFR antagonists. In this review, we provide comprehensive evidence regarding the PAF/PAFR signaling pathway, highlighting the effectiveness of various classes of PAF and PAFR inhibitors and antagonists across multiple cancer models. Notably, the synergistic effects of PAF and PAFR antagonists in enhancing the efficacy of chemotherapy and radiation therapy in several experimental cancer models are also discussed. Overall, the synthesis of literature review indicates that targeting the PAF/PAFR axis represents a promising approach for cancer treatment and also exerts synergy with chemotherapy and radiation therapy.Keywords：Platelet-activating factor (PAF);Platelet-activating factor-receptor (PAFR);Antagonists;Inhibitors;Cancer;Cell signaling pathways;Radiation therapy;Chemotherapy44|1|0Updated：2025-12-13 -
Targeting the central and peripheral nervous system to regulate bone homeostasis:mechanisms and potential therapies AI Introduction
“In the field of bone research, this paper reviews the connection between the nervous system and bone metabolism, either intact or after injury. It explores the relationship between specific brain nuclei and bone homeostasis, the characteristics of bone innervation and nerve subtypes, and the molecular features and regulatory functions of these nerves. The paper also summarizes available translational approaches that utilize nerve function to improve bone homeostasis and promote bone regeneration.”Abstract：The skeleton is innervated by different types of nerves and receives signaling from the nervous system to maintain homeostasis and facilitate regeneration or repair. Although the role of peripheral nerves and signals in regulating bone homeostasis has been extensively investigated, the intimate relationship between the central nervous system and bone remains less understood, yet it has emerged as a hot topic in the bone field. In this review, we discussed clinical observations and animal studies that elucidate the connection between the nervous system and bone metab-olism, either intact or after injury. First, we explored mechanistic studies linking specific brain nuclei with bone home-ostasis, including the ventromedial hypothalamus, arcuate nucleus, paraventricular hypothalamic nucleus, amygdala, and locus coeruleus. We then focused on the characteristics of bone innervation and nerve subtypes, such as sensory, sympathetic, and parasympathetic nerves. Moreover, we summarized the molecular features and regulatory functions of these nerves. Finally, we included available translational approaches that utilize nerve function to improve bone homeostasis and promote bone regeneration. Therefore, considering the nervous system within the context of neu-romusculoskeletal interactions can deepen our understanding of skeletal homeostasis and repair process, ultimately benefiting future clinical translation.Keywords：Osteoporosis;central nervous system;Brain nuclei;Peripheral nerve fiber;Bone homeostasis40|0|0Updated：2025-12-13
REVIEW
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AKR1C3 as a therapeutic target to overcome erlotinib resistance in lung adenocarcinoma AI Introduction
“In the field of xxx, expert xx has made significant research progress. By establishing the xx system/exploring the xx topic/verifying the xx conjecture, they have provided solutions to address xx problems/open up a new direction for xx research/lay a foundation for the construction of the xx system.”Keywords：AKR1C3;Erlotinib resistance;Epidermal growth factor receptor (EGFR) mutation;Lung adenocarcinoma(LUAD);Therapeutic target48|0|0Updated：2025-12-13 -
Fostering hope and recovery: enhancing psychological resources in military personnel with post-traumatic stress disorder AI Introduction
“In the field of xxx, expert xx has made significant research progress. By establishing the xx system/exploring the xx topic/verifying the xx conjecture, xx has provided solutions to address xx problems/open up a new direction for xx research/lay a foundation for the construction of the xx system.”Keywords：Post-traumatic stress disorder;Hope;Self-esteem;Positive mental health;Well-being;Military personnel;Rehabilitation47|1|0Updated：2025-12-13
LETTER TO THE EDITOR
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