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"Zuo, He"
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Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis
Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal fibrotic lung disease that occurs primarily in middle-aged and elderly adults. It is a major cause of morbidity and mortality. With an increase in life expectancy, the economic burden of IPF is expected to continuously rise in the near future. Although the exact pathophysiological mechanisms underlying IPF remain not known. Significant progress has been made in our understanding of the pathogenesis of this devastating disease in last decade. The current paradigm assumes that IPF results from sustained or repetitive lung epithelial injury and subsequent activation of fibroblasts and myofibroblast differentiation. Persistent myofibroblast phenotype contributes to excessive deposition of the extracellular matrix (ECM) and aberrant lung repair, leading to tissue scar formation, distortion of the alveolar structure, and irreversible loss of lung function. Treatments of patients with IPF by pirfenidone and nintedanib have shown significant reduction of lung function decline and slowing of disease progression in patients with IPF. However, these drugs do not cure the disease. In this review, we discuss recent advances on the pathogenesis of IPF and highlight the development of novel therapeutic strategies against the disease.
Journal Article
Atractylenolide III ameliorates spinal cord injury in rats by modulating microglial/macrophage polarization
Background Inflammatory reactions induced by spinal cord injury (SCI) are essential for recovery after SCI. Atractylenolide III (ATL‐III) is a natural monomeric herbal bioactive compound that is mainly derived in Atractylodes macrocephala Koidz and has anti‐inflammatory and neuroprotective effects. Objective Here, we speculated that ATL‐III may ameliorate SCI by modulating microglial/macrophage polarization. In the present research, we focused on investigating the role of ATL‐III on SCI in rats and explored the potential mechanism. Methods The protective and anti‐inflammatory effects of ATL‐III on neuronal cells were examined in a rat SCI model and lipopolysaccharide (LPS)‐stimulated BV2 microglial line. The spinal cord lesion area, myelin integrity, and surviving neurons were assessed by specific staining. Locomotor function was evaluated by the Basso, Beattie, and Bresnahan (BBB) scale, grid walk test, and footprint test. The activation and polarization of microglia/macrophages were assessed by immunohistofluorescence and flow cytometry. The expression of corresponding inflammatory factors from M1/M2 and the activation of relevant signaling pathways were assessed by Western blotting. Results ATL‐III effectively improved histological and functional recovery in SCI rats. Furthermore, ATL‐III promoted the transformation of M1 into M2 and attenuated the activation of microglia/macrophages, further suppressing the expression of corresponding inflammatory mediators. This effect may be partly mediated by inhibition of neuroinflammation through the NF‐κB, JNK MAPK, p38 MAPK, and Akt pathways. Conclusion This study reveals a novel effect of ATL‐III in the regulation of microglial/macrophage polarization and provides initial evidence that ATL‐III has potential therapeutic benefits in SCI rats. ATL‐III has potential therapeutic benefits in promoting histological and functional repair in rats after SCI. This effect may be partly mediated by inhibiting neuroinflammation induced by microglial polarization through the NF‐κB, JNK MAPK, p38 MAPK, and Akt pathways.
Journal Article
Transcriptome profile of rat genes in injured spinal cord at different stages by RNA-sequencing
Background
Spinal cord injury (SCI) results in fatal damage and currently has no effective treatment. The pathological mechanisms of SCI remain unclear. In this study, genome-wide transcriptional profiling of spinal cord samples from injured rats at different time points after SCI was performed by RNA-Sequencing (RNA-Seq). The transcriptomes were systematically characterized to identify the critical genes and pathways that are involved in SCI pathology.
Results
RNA-Seq results were obtained from total RNA harvested from the spinal cords of sham control rats and rats in the acute, subacute, and chronic phases of SCI (1 day, 6 days and 28 days after injury, respectively;
n
= 3 in every group). Compared with the sham-control group, the number of differentially expressed genes was 1797 in the acute phase (1223 upregulated and 574 downregulated), 6590 in the subacute phase (3460 upregulated and 3130 downregulated), and 3499 in the chronic phase (1866 upregulated and 1633 downregulated), with an adjusted
P
-value <0.05 by DESeq. Gene ontology (GO) enrichment analysis showed that differentially expressed genes were most enriched in immune response, MHC protein complex, antigen processing and presentation, translation-related genes, structural constituent of ribosome, ion gated channel activity, small GTPase mediated signal transduction and cytokine and/or chemokine activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most enriched pathways included ribosome, antigen processing and presentation, retrograde endocannabinoid signaling, axon guidance, dopaminergic synapses, glutamatergic synapses, GABAergic synapses, TNF, HIF-1, Toll-like receptor, NF-kappa B, NOD-like receptor, cAMP, calcium, oxytocin, Rap1, B cell receptor and chemokine signaling pathway.
Conclusions
This study has not only characterized changes in global gene expression through various stages of SCI progression in rats, but has also systematically identified the critical genes and signaling pathways in SCI pathology. These results will expand our understanding of the complex molecular mechanisms involved in SCI and provide a foundation for future studies of spinal cord tissue damage and repair.
The sequence data from this study have been deposited into Sequence Read Archive (
http://www.ncbi.nlm.nih.gov/sra
; accession number PRJNA318311).
Journal Article
Comparison of Tc-99 m scintigraphic method and radiological method for colon transmit assessment in patients with functional constipation
Background
The methods for assessing colonic transit in patients with functional constipation include the radiological method and Tc-99m scintigraphic method. This study aims to validate the practicality and accuracy of the Tc-99m scintigraphic method in evaluating colon transit, while also exploring the significance of the geometric center (GC).
Methods
Our study is a single-center, retrospective analysis. We examined the medical records of 47 patients, who underwent colonic transit by the Tc-99m scintigraphic method and the radiological method for investigation of chronic constipation. Geometric center (GC) and transmit index (TI) were calculated respectively in these two methods. The patients were divided into four types of constipation: normal transit constipation (NTC), slow transit constipation (STC), defecatory disorders (DD) and STC combined with DD.
Results
The results of the Tc-99m scintigraphic method and radiological method were consistent in the diagnosis of slow colon transmission (Kappa value = 0.718,
P
< 0.001). TI and 48-h GC were positively correlated (r = 0.657,
p
= 0.001). Patients with DD exhibited higher 24-h GC and 48-h GC values compared to those with STC.
Conclusion
Tc-99m scintigraphic method can be used to evaluate colonic transit in patients with constipation, and GC values may be used to distinguish the types of constipation.
Journal Article
Managing Cancer and Living Meaningfully (CALM) Intervention on Chemotherapy-Related Cognitive Impairment in Breast Cancer Survivors
Objective: To evaluate the effectiveness and feasibility of Managing Cancer and Living Meaningfully (CALM), which is used to reduce chemotherapy-related cognitive impairment (CRCI), relieve psychological distress, and improve quality of life (QOL) in Chinese breast cancer survivors (BCs). Methods: Seventy-four BCs were enrolled in this study. All patients were randomly assigned to either the CALM group or the care as usual (CAU) group. All patients were evaluated by the Functional Assessment of Cancer Therapy–Cognitive Function (FACT-Cog), Distress Thermometer (DT), and the Functional Assessment of Cancer Therapy–Breast (FACT-B) before and after CALM or CAU application to BCs with CRCI. We compared the differences in all these scores between the CALM group and the control group and analyzed the correlation between cognitive function and QOL. Results: Compared with the CAU group, the performance of the CALM group on the FACT-Cog, DT, and FACT-B showed significant differences before and after CALM (t = −18.909, −5.180, −32.421, P = .000, .000, .000, respectively). Finally, there was a positive correlation between cognitive function and QOL in breast cancer patients before (r = 0.579, P = .000) and after (r = 0.797, P = .000) treatment. Conclusions: The present results indicated that CALM has salutary effects on the improvement of cognitive impairment and QOL and relieves psychological distress in breast cancer patients, which may be due to a positive correlation between psychological distress and cognitive function or QOL.
Journal Article
Metformin-associated gut microbiota remodeling correlates with reinvigorated splenic immunity in aged mice: microbiome-immune crosstalk via the gut-spleen axis
Immunosenescence involves age-related immune decline and chronic inflammation, with the spleen serving as a critical hub for immune dysregulation. While gut microbiota influences systemic immunity, its specific role and the potential existence of a gut-spleen axis in mediating splenic aging remains unclear. Therefore, we investigated whether metformin, a microbiota-modulating geroprotective drug, alleviates splenic immunosenescence in aged mice, specifically exploring the link between gut microbiota remodeling and splenic immune rejuvenation.
Aged C57BL/6 mice (15-month-old) received oral metformin (300 mg/kg/day) or vehicle for 5 months. Systemic toxicity and metabolism were monitored. Splenic immune subsets were analyzed using flow cytometry and immunohistochemistry. Gut microbiota composition (16S rRNA sequencing), cytokine levels (RT-qPCR), and functional pathways were assessed.
Metformin caused no hepatorenal toxicity or weight changes. Treated mice exhibited increased cytotoxic T cells (Tc) and macrophages in the spleen, with reduced Th/Tc ratios and M1/M2 polarization. Pro-inflammatory cytokines (Ifng, Il17a, Il1b, Il6) decreased, while anti-inflammatory markers (Arg1, Tgfb1) rose. Gut microbiota showed enriched
,
, and
, but reduced
.
negatively correlated with pro-inflammatory cytokines, whereas
and
linked to pro-inflammatory responses. Functional prediction analysis based on 16S rRNA sequencing data indicated upregulation of bile acid metabolism and oxidative phosphorylation pathways.
Metformin reshapes the gut microbiota, which is associated with mitigation of age-associated splenic immune dysregulation, favoring anti-inflammatory macrophage polarization and cytotoxic T cell expansion. Critically, our findings establish the gut-spleen axis as a key mediator of splenic immunosenescence and a novel therapeutic target, which positions metformin as a promising microbiota-directed geroprotective agent. Future research should prioritize mechanistic dissection of gut-spleen communication and clinical validation of metformin's geroprotective efficacy in human populations.
Journal Article
CRID3, a blocker of apoptosis associated speck like protein containing a card, ameliorates murine spinal cord injury by improving local immune microenvironment
Background
After spinal cord injury (SCI), destructive immune cell subsets are dominant in the local microenvironment, which are the important mechanism of injury. Studies have shown that inflammasomes play an important role in the inflammation following SCI, and apoptosis-associated speck-like protein containing a card (ASC) is the adaptor protein shared by inflammasomes. Therefore, we speculated that inhibiting ASC may improve the local microenvironment of injured spinal cord. Here, CRID3, a blocker of ASC oligomerization, was used to study its effect on the local microenvironment and the possible role in neuroprotection following SCI.
Methods
Murine SCI model was created using an Infinite Horizon impactor at T9 vertebral level with a force of 50 kdynes and CRID3 (50 mg/kg) was intraperitoneally injected following injury. ASC and its downstream molecules in inflammasome signaling pathway were measured by western blot. The immune cell subsets were detected by immunohistofluorescence (IHF) and flow cytometry (FCM). The spinal cord fibrosis area, neuron survival, myelin preservation, and functional recovery were assessed.
Results
Following SCI, CRID3 administration inhibited inflammasome-related ASC and caspase-1, IL-1β, and IL-18 activation, which consequently suppressed M1 microglia, Th1 and Th1Th17 differentiation, and increased M2 microglia and Th2 differentiation. Accordingly, the improved histology and behavior have also been found.
Conclusions
CRID3 may ameliorate murine SCI by inhibiting inflammasome activation, reducing proinflammatory factor production, restoring immune cell subset balance, and improving local immune microenvironment, and early administration may be a promising therapeutic strategy for SCI.
Journal Article
Bone Marrow Mesenchymal Stem Cells (BM-MSCs) Improve Heart Function in Swine Myocardial Infarction Model through Paracrine Effects
Stem cells are promising for the treatment of myocardial infarction (MI) and large animal models should be used to better understand the full spectrum of stem cell actions and preclinical evidences. In this study, bone marrow mesenchymal stem cells (BM-MSCs) were transplanted into swine heart ischemia model. To detect glucose metabolism in global left ventricular myocardium and regional myocardium, combined with assessment of cardiac function, positron emission tomography-computer tomography (PET-CT) and magnetic resonance imaging (MRI) were performed. To study the changes of glucose transporters and glucose metabolism-related enzymes and the signal transduction pathway, RT-PCR, Western-blot, and immunohistochemistry were carried out. Myocardium metabolic evaluation by PET-CT showed that mean signal intensity (MSI) increased in these segments at week 4 compared with that at week 1 after BM-MSCs transplantation. Moreover, MRI demonstrated significant function enhancement in BM-MSCs group. The gene expressions of glucose transporters (GLUT1, GLUT4), glucose metabolism-related enzymes phosphofructokinase (PFK), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) and 70-kDa ribosomal protein S6 kinase (p70s6k) in BM-MSCs injected areas were up-regulated at week 4 after BM-MSCs transplantation and this was confirmed by Western-blot and immunohistochemistry. In conclusions, BM-MSCs transplantation could improve cardiac function in swine MI model by activation of mTOR signal transduction pathway.
Journal Article
Dual role of Lyz2-positive myeloid cells in traumatic brain injury: acute anti-inflammatory effects vs. chronic neurological deterioration
Neuroinflammation is a critical factor contributing to secondary brain injury following traumatic brain injury (TBI). This process engages diverse cell types within the central nervous system (CNS), including significant infiltration of myeloid lineage cells-primarily neutrophils and macrophages-during the acute and subacute phases of TBI. These myeloid-derived cells represent a major population that critically influences the development and progression of neuroinflammation. Microglia and peripherally infiltrating macrophages exhibit polarization phenotypes that play a pivotal role in modulating inflammatory changes. Due to their functional and phenotypic similarities, their distinct contributions to the inflammatory response in TBI remain a subject of considerable debate. Lysozyme 2 (Lyz2) is a well-established marker for myeloid lineage cells (including monocytes, macrophages, and neutrophils) in mice, allowing specific targeting and depletion of these cells to dissect their functional roles in TBI.
In the present study, we investigated the trend of inflammatory factors during the early stage of TBI using Lyz2-IRES-DTREGFP transgenic mice, which specifically target and deplete Lyz2-positive myeloid cells. Tissue samples for RT-qPCR and flow cytometry were harvested from the perilesional cortex (within a 2-mm radius of the impact site) and the underlying hippocampus.
Our findings revealed a considerable reduction in the expression of pro-inflammatory factors (e.g., IL-1β, iNOS, IL-6, IFN-γ) and an increase in the expression of anti-inflammatory factors (e.g., IL-4, IL-10, IL-13, Arg-1). Furthermore, we observed a shift in polarization phenotypes, characterized by a decreased proportion of M1 macrophages and an increased proportion of M2 macrophages. However, during the chronic phase, behavioral and histological analyses revealed worse outcomes. These findings demonstrate that targeted depletion of Lyz2-positive myeloid cells during acute TBI attenuates neuroinflammation. However, this early immunomodulatory shift correlates paradoxically with exacerbated chronic neurological deficits, suggesting that transient suppression of myeloid-driven inflammation may disrupt long-term reparative processes critical for functional recovery after TBI.
Journal Article