Genomics, Proteomics & Bioinformatics•2024•DOI: 10.1093/gpbjnl/qzae019
Lysine post-translational modifications (PTMs) are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins. Dysregulation of lysine PTMs is implicated in many diseases, and targeting lysine PTM regulatory factors, including writers, erasers, and readers, has become an effective strategy for disease therapy. The continuing development of mass spectrometry (MS) technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of PTMs. The global characterization of lysine PTMs is crucial for deciphering the regulatory networks, molecular functions, and mechanisms of action of lysine PTMs. In this review, we focus on lysine PTMs, and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS technologies. We also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy.
Stem Cell Research & Therapy•2025•DOI: 10.1186/s13287-025-04258-w
Background Tumors and injuries often lead to large mandibular defects. Accelerating the osteogenesis of large bone defect areas is a major concern in current research. In this study, dental pulp mesenchymal stem cells (DPSCs) were used as seed cells, and the local pulsatile parathyroid hormone (PTH) delivery system was used as an osteogenic-inducing active ingredient to act on DPSCs and osteoblasts, which were applied to the jaw defect area to evaluate its therapeutic effect on bone regeneration. Methods Pulsatile delivery systems, both with and without PTH, were developed following the protocols outlined in our previous study. In vitro, the biocompatibility of the pulsatile delivery system with DPSCs was assessed using the Cell Counting Kit-8 (CCK8) assay and live/dead cell staining. Osteogenic differentiation was evaluated through alkaline phosphatase staining and alizarin red staining. In vivo, critical bone defects with a diameter of 10 mm were created in the mandibles of white rabbits. The osteogenic effect was further assessed through gross observation, X-ray imaging, and histological examination. Results In vitro experiments using CCK8 assays and live/dead cell staining demonstrated that DPSCs successfully adhered to the surface of the PTH pulsatile delivery system, showing no significant difference compared to the control group. Furthermore, alkaline phosphatase staining and Alizarin Red staining confirmed that the localized pulsatile parathyroid hormone delivery system effectively induced the differentiation of DPSCs into osteoblasts, leading to the secretion of abundant calcium nodules. Animal studies further revealed that the PTH pulsatile delivery system promoted the osteogenic differentiation of DPSCs, facilitating the repair of critical mandibular bone defects.
Stem Cell Research & Therapy•2025•DOI: 10.1186/s13287-025-04549-2
Adipose-derived stem cells (ADSCs) are a specific type of mesenchymal stem cells (MSCs) obtained easily from adipose tissue (AT). Compared with MSCs, ADSCs are easier to obtain, have fewer ethical issues, and have a higher proliferative capacity, which makes them a promising type of stem cell in regenerative medicine. ADSCs possess impressive capabilities in cell regeneration as well as differentiation, making them promising candidates for injury repair, tissue regeneration and alleviation of inflamed tissues. At present, most clinical studies on ADSCs focus on the treatment of wounds, multiple sclerosis, soft tissue trauma, aging, diabetes, Parkinson’s disease, bone and cartilage regeneration, stroke, and spinal cord injury, while its clinical applications in the gastrointestinal tract are relatively few. Therefore, this review summarizes the findings of preclinical experiments, clinical trials, and areas that may require further development of ADSCs in the treatment of digestive disorders, including inflammatory bowel disease (IBD), colorectal cancer (CRC), colorectal fibrosis, hepatocellular carcinoma, hepatic fibrosis, gastric cancer (GC), gastrostomy closure and radiation-induced proctitis. The review is concluded by discussing the goals for improvement and future directions for ADSCs before large-scale clinical application.
Stem Cell Research & Therapy•2026•DOI: 10.1186/s13287-025-04862-w
Using adipose-derived stem cells (ADSCs) has recently become a crucial approach for treating bone defects owing to their ease of accessibility and substantial differentiation potential. N6-methyladenosine (m6A) modification greatly influences biological processes and determines the differentiation fate of stem cells. However, the specific mechanisms by which m6A modification influences the osteogenic differentiation of ADSCs remain unclear. We identified FOXO1 as the key m6A-modified gene during the osteogenesis of ADSCs. Furthermore, demethylase FTO enhanced RUNX2 expression while inhibiting PPARG expression by modifying FOXO1, thereby facilitating ADSC osteogenesis. FTO knockdown inhibited ADSC migration and proliferation and impaired osteogenesis by suppressing FOXO1. At the mechanistic level, we first revealed that FTO was exported to the cytoplasm and then directly bound with FOXO1 mRNA at its 1760th bp site. Consistent use of non-steroidal anti-inflammatory drugs (NSAIDs) containing FTO inhibitors impeded ADSC-mediated bone formation both in vivo and in vitro. In summary, our study reveals the role of m6A modification based on the FTO–FOXO1–RUNX2/PPARG axis in regulating the osteogenic differentiation of ADSCs, thereby improving the clinical use of ADSCs and providing strategies for related drug applications in bone regeneration.
Stem Cell Research & Therapy•2024•DOI: 10.1186/s13287-024-03898-8
Background Hepatic progenitor cells serve not only as the origin of combined hepatocellular cholangiocarcinoma (cHCC-CCA) but are also responsible for malignancy recurrence after surgical resection. Nucleophosmin 1 (NPM1) has been implicated in cancer metastasis and poor prognosis. This study aimed to determine the expression of NPM1 by hepatic progenitor cells in cHCC-CCA and the effects of targeting NPM1 on hepatic progenitor cells and BEL-7402 cells with characteristics of both progenitor cells and cHCC-CCA. Methods First, NPM1 was detected by RT‒PCR, western blotting, and double-immunofluorescence staining in cHCC-CCA tissues. NPM1 expression was subsequently analysed in rat hepatic progenitor cells cultured in vitro and in interleukin 6 (IL6)-treated cells. The effects and mechanism of NPM1 on hepatic progenitor cells were determined by knocking down NPM1 and performing RNA sequencing analysis. Finally, NSC348884, a small-molecule inhibitor that disrupts NPM1 dimer formation, was used to confirm the function of NPM1 in BEL-7402 cells. Results Both human hepatic progenitor cells in cHCC-CCA tissues and rat in vitro cultured hepatic progenitor cells highly expressed NPM1. IL6, a cytokine involved in the malignant transformation of hepatic progenitor cells, dose-dependently increased NPM1 and PCNA expression. Knocking down NPM1 reduced IL6R transcription (P < 0.0001) and inhibited the proliferation (P = 0.0065) of hepatic progenitor cells by suppressing the mTOR signalling pathway and activating the apoptosis pathway. Furthermore, knocking down NPM1 in hepatic progenitor cells resulted in more apoptotic cells (7.33 ± 0.09% vs. 3.76 ± 0.13%, P < 0.0001) but fewer apoptotic cells in the presence of NSC348884 (47.57 ± 0.49% vs. 63.40 ± 0.05%, P = 0.0008) than in the control cells, suggesting that low-NPM1-expressing cells are more resistant to NSC348884. In addition, NSC348884 induced the apoptosis of BEL-7402 cells with an IC50 of 2.77 μmol/L via the downregulation of the IL-6R and mTOR signalling pathways and inhibited the growth of BEL-7402 cells in a subcutaneous xenograft tumour model (P = 0.0457). Conclusions Targeting NPM1 inhibits proliferation and induces apoptosis in hepatic progenitor cells and BEL-7402 cells, thus serving as a potential therapy for cHCC-CCA.
Stem Cell Research & Therapy•2024•DOI: 10.1186/s13287-024-03793-2
Background Cartilage is a kind of avascular tissue, and it is difficult to repair itself when it is damaged. In this study, we investigated the regulation of chondrogenic differentiation and vascular formation in human jaw bone marrow mesenchymal stem cells (h-JBMMSCs) by the long-chain noncoding RNA small nucleolar RNA host gene 1 (SNHG1) during cartilage tissue regeneration. Methods JBMMSCs were isolated from the jaws via the adherent method. The effects of lncRNA SNHG1 on the chondrogenic differentiation of JBMMSCs in vitro were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), Pellet experiment, Alcian blue staining, Masson’s trichrome staining, and modified Sirius red staining. RT-qPCR, matrix gel tube formation, and coculture experiments were used to determine the effect of lncRNA SNHG1 on the angiogenesis in JBMMSCs in vitro. A model of knee cartilage defects in New Zealand rabbits and a model of subcutaneous matrix rubber suppositories in nude mice were constructed for in vivo experiments. Changes in mitochondrial function were detected via RT-qPCR, dihydroethidium (DHE) staining, MitoSOX staining, tetramethyl rhodamine methyl ester (TMRM) staining, and adenosine triphosphate (ATP) detection. Western blotting was used to detect the phosphorylation level of signal transducer and activator of transcription 3 (STAT3). Results Alcian blue staining, Masson’s trichrome staining, and modified Sirius Red staining showed that lncRNA SNHG1 promoted chondrogenic differentiation. The lncRNA SNHG1 promoted angiogenesis in vitro and the formation of microvessels in vivo. The lncRNA SNHG1 promoted the repair and regeneration of rabbit knee cartilage tissue. Western blot and alcian blue staining showed that the JAK inhibitor reduced the increase of STAT3 phosphorylation level and staining deepening caused by SNHG1. Mitochondrial correlation analysis revealed that the lncRNA SNHG1 led to a decrease in reactive oxygen species (ROS) levels, an increase in mitochondrial membrane potential
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026055
Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer’s disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Atractylodes macrocephala Koidz., exhibits multimodal bioactivities with demonstrated anti-inflammatory and neuroprotective properties. To explore its therapeutic potential against AD pathology, we use high-fat diet (HFD)-fed ApoE knockout (ApoE–/–) mice treated with or without AI for 12 weeks. Integrated bioinformatics analyses and experimental validation reveal that AI treatment markedly attenuates systemic lipid dyshomeostasis, particularly cerebral lipid deposition, suppresses neuroinflammation via downregulation of M1 macrophage polarization markers, and restores cognitive function through neuronal preservation in hippocampal regions. Mechanistically, AI orchestrates cholesterol efflux by up-regulating ATP-binding cassette transporter A1 (ABCA1) and liver X receptor (LXR) expression, while concurrently modulating the abundance of arginine biosynthesis metabolites (urea, malic acid, and creatinine) to rebalance neurovascular homeostasis. Notably, western blot and RT-qPCR analyses reveal that AI differentially regulates key enzymes including arginase 1 (ARG1) and simultaneously upregulates the expression of neuronal nitric oxide synthase (nNOS). Further molecular docking and surface plasmon resonance (SPR) analyses confirm the direct binding of AI to ARG1, indicating a novel neuroprotective mechanism involving the modulation of arginine metabolism. These findings delineate the pleiotropic effects of AI against AD pathology and establish a preclinical foundation for the development of AI-based therapeutics targeting neurodegenerative-cardiovascular comorbidities.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025042
This study elucidates the mechanisms by which cancer-associated fibroblast (CAF)-derived platelet-derived growth factor C (PDGFC) promotes the progression of lung adenocarcinoma (LUAD) and explores the impact of PDGFC on immune regulation within the tumor microenvironment (TME). Our results show that there is higher expression of PDGFC in CAFs than in nontumor tissue fibroblasts (NFs) and that higher expression of PDGFC is correlated with poor prognosis in LUAD patients. Furthermore, CAF-derived PDGFC promotes epithelial-mesenchymal transition (EMT) in cancer cells as well as matrix metalloproteinase 2 (MMP2) expression through the PDGF receptor A (PDGFRA)-mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Moreover, our study demonstrates that CAF-derived PDGFC is essential for the activation and infiltration of fibroblasts in the TME, as well as the inflammatory infiltration of different immune cell types and the immunosuppressive conditions within the TME. In particular, PDGFC induces increased PDGFRA expression in both tumor cells and fibroblasts, which can lead to reciprocally positive feedback to accelerate malignant tumor progression. This discovery provides a novel TME-targeted strategy for LUAD treatment.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2025164
Emerging biochemical and genetic evidence has firmly established aberrant protein glycosylation as a critical regulator of oncogenic transformation, with glycocalyx remodeling profoundly influencing tumor microenvironment dynamics and metastatic progression. Despite the well-documented association between metastatic dissemination and poor clinical outcomes in patients with colorectal cancer, the underlying molecular mechanisms remain incompletely characterized. Through integrative analysis of single-cell RNA sequencing data from a public database, we identify the Golgi-resident α-1,2-mannosidase MAN1A1 as a consistently upregulated enzyme in malignant epithelial cells derived from colorectal cancer liver metastases. Clinically, elevated MAN1A1 expression is correlated with reduced overall survival, suggesting that MAN1A1 is both a prognostic biomarker and therapeutic target for colorectal cancer liver metastases. Genetic manipulation of MAN1A1 in colorectal cancer cells demonstrates that although the proliferation capacity of colorectal cancer cells remains unchanged, MAN1A1 overexpression significantly enhances migratory and invasive capacities in transwell assays, suggesting its specific involvement in metastatic progression. Mechanistic investigations reveal that MAN1A1 exerts its pro-metastatic effects by significantly prolonging the TGFBR2 protein half-life. Together, our work identifies MAN1A1 as both a prognostic biomarker and a promising therapeutic target, highlighting the critical role of glycan remodeling in the metastatic progression of colorectal cancer.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024235
Activated astrocytes and their associated inflammatory responses play critical roles in the pathogenesis of hypoxic-ischemic brain damage (HIBD). Gastrodin (GAS), an anti-inflammatory herbal agent, is known to suppress microglial activation. Here, we investigate whether it exerts a similar effect on activated astrocytes and whether it acts through S100B/RAGE-Smad3 signaling. The expression changes of S100B/RAGE-Smad3 signaling pathway-related proteins, inflammatory factors and A1/A2 astrocyte markers were detected by ELISA, western blot analysis, immunofluorescence and immunohistochemistry. The results show that GAS decreases the expression of sRAGE in the brain tissue and S100B in the serum and brain tissue of HIBD mice. However, it promotes the expression of sRAGE in the serum of HIBD mice. Moreover, GAS inhibits the expressions of RAGE, p-Smad3, TNF-α, and C3 (A1 astrocyte marker), and promotes the expressions of S100A10 (A2 astrocyte marker) and BDNF in HIBD model mice, as well as in oxygen glucose deprivation (OGD)-treated TNC-1 astrocytes. The immunofluorescence and immunohistochemical results of RAGE and p-Smad3, as well as the immunofluorescence results of C3 and S100A10, reveal the same trend. Interestingly, FPS-ZM1 (a specific inhibitor of RAGE) inhibits the expressions of p-Smad3, TNF-α, C3, and S100A10, but promotes that of BDNF compared with those in the OGD group. The combination of GAS and FPS-ZM1 further decreases the expression of C3. These results indicate that GAS can inhibit the activation of Smad3 through S100B/RAGE signaling and regulate the expression of A1/A2-type astrocytes.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024183
Traumatic brain injury (TBI) is a recognized global public health problem. However, there are still limitations in the available therapeutic approaches and a lack of clinically effective drugs. Therefore, an in-depth exploration of the secondary pathological mechanism of TBI and the identification of new effective drugs are urgently needed. Cannabidiol (CBD), a component derived from the cannabis plant, has potential therapeutic effects on neurological diseases and has received increasing attention. However, few reports on CBD intervention in TBI patients exist. Here, we use the Feeney free-fall method to establish a rat TBI model. CBD significantly improves neurological deficit scores, neuronal damage and blood-brain barrier permeability in rats and significantly inhibits the expressions of the brain injury markers S-100β and NSE. Mechanistically, CBD attenuates TBI-induced astrocyte activation, reduces inflammation, and attenuates the expressions of inflammatory prostaglandin system indicators. The use of TG6-10-1 (EP2 inhibitor) and H-89 (PKA inhibitor) indicates that CBD attenuates TBI-induced neurological damage via the PGE2-EP2-cAMP-PKA signaling pathway. Overall, this research provides a novel drug candidate for the treatment of clinical brain trauma.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2024091
Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. Immunocompromised individuals infected by HEV are prone to chronic hepatitis and increase the risk of hepato-cellular carcinoma (HCC). Inhibitor of growth family member 5 (ING5) is a tumor suppressor that is expressed at low levels in cancer tumors or cells. However, the underlying relationship between ING5 and HEV infection is unclear. In the present study, acute and chronic HEV animal models are used to explore the interaction between ING5 and HEV. Notably, the expression of ING5 is significantly increased in both the livers of acute HEV-infected BALB/c mice and chronic HEV-infected rhesus macaques. In addition, the relationship between HEV infection and ING5 expression is further identified in human hepatoma (HepG-2) cells. In conclusion, HEV infection strongly upregulates ING5 expression both in vivo and in vitro, which has significant implications for further understanding the pathogenic mechanism of HEV infection.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2024050
The interaction between bacteria and the host plays a vital role in the initiation and progression of systemic diseases, including gastrointestinal and oral diseases, due to the secretion of various virulence factors from these pathogens. GroEL, a potent virulence factor secreted by multiple oral pathogenic bacteria, is implicated in the damage of gingival epithelium, periodontal ligament, alveolar bone and other peripheral tissues. However, the underlying biomechanism is still largely unknown. In the present study, we verify that GroEL can trigger the activation of NLRP3 inflammasome and its downstream effector molecules, IL-1β and IL-18, in human periodontal ligament stem cells (hPDLSCs) and resultantly induce high activation of gelatinases (MMP-2 and MMP-9) to promote the degradation of extracellular matrix (ECM). GroEL-mediated activation of the NLRP3 inflammasome requires the participation of Toll-like receptors (TLR2 and TLR4). High upregulation of TLR2 and TLR4 induces the enhancement of NF-κB (p-p65) signaling and promotes its nuclear accumulation, thus activating the NLRP3 inflammasome. These results are verified in a rat model with direct injection of GroEL. Collectively, this study provides insight into the role of virulence factors in bacteria-induced host immune response and may also provide a new clue for the prevention of periodontitis.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024210
Esophageal squamous cell carcinoma (ESCC) is one of the most common forms of malignancy worldwide. However, there is currently a lack of effective chemotherapeutic drugs for ESCC. Ivermectin is a broad-spectrum antiparasitic drug with notable antitumor activity. However, the cellular and molecular mechanisms by which ivermectin inhibits cancer growth remain unclear. In this study, we elucidate the role of ivermectin in ESCC suppression by activating the endoplasmic reticulum (ER) stress and autophagy pathways. In transcriptome analyses, we find that activating transcription factor 4 (ATF4) and DNA damage inducible transcript 3 (DDIT3) are involved in the activation of ER stress by ivermectin. Moreover, ivermectin treatment suppresses the growth of ESCC xenograft tumors in nude mice. Taken together, our results establish the antitumor molecular role of ivermectin in targeting the ER stress-autophagy pathway and suggest that ivermectin is a potential drug candidate for the treatment of ESCC.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2025139
Sepsis-associated acute liver injury (SALI) is a frequent and clinically severe complication of sepsis, in which inflammatory responses and oxidative stress are involved. Angelicin (ANG), one of the main active components in the traditional Chinese medicine Psoralea corylifolia Linn., has anti-inflammatory and antioxidant bioactivities. In this study, the protective effect of ANG on SALI and its specific mechanism are investigated by establishing a mouse model of caecal ligation and puncture (CLP)-induced SALI and an in vitro sepsis model in LPS-stimulated AML12 cells. These results show that ANG can alleviate liver injury and improve liver function in SALI mice. ANG decreases the mRNA expression levels of the pro-inflammatory factors Il-1β, Il-6, and Tnf-α and increases the mRNA expression level of the anti-inflammatory factor Il-10, which suggests its anti-inflammatory effects. The results of the biochemical kit assay and DHE staining show that ANG can decrease the levels of MDA and ROS and increase the level of GSH and the activities of CAT and SOD, which suggests that ANG has antioxidant effects. Mechanistically, ANG exerts anti-inflammatory effects by inhibiting the NF-κB and p38 MAPK pathways and exerting antioxidant effects by activating the Nrf2/Keap1 pathway. Additionally, cell transfection experiments indicate that activation of the Nrf2/Keap1 pathway by ANG may depend on the inhibition of the NF-κB pathway. In conclusion, ANG attenuates SALI by inhibiting the NF-κB and p38 MAPK pathways, thereby activating the Nrf2/Keap1 pathway and making it a promising therapeutic intervention for SALI.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024199
The renin-angiotensin system (RAS) is a crucial regulatory mechanism for cardiovascular function. The angiotensin II (Ang II) type 1 receptor (AT1R) is the principal receptor responsible for mediating RAS function. AT1R belongs to the G protein-coupled receptor (GPCR) family and is present in multiple tissues, including vascular smooth muscle, endothelium, heart, brain, kidney, adrenal gland, and adipose tissue. Physiologically, AT1R mediates second messenger signaling through classical G proteins. Ang II binding to AT1R predominantly activates Gq/11, leading to the activation of phospholipase C (PLC), which results in the production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DG). Then, increased Ca2+ is released from the sarcoplasmic reticulum to mediate the processes of vasoconstriction, enhance cardiac contractility, regulate water‒salt balance, etc. Under pathological conditions, AT1R aberrantly activates G proteins, including mitogen-activated protein kinases (MAPKs: ERK1/2, JNK, and p38MAPK), receptor tyrosine kinases (PDGF, EGFR, and insulin receptor), non-receptor tyrosine kinases [Src, JAK/STAT, and focal adhesion kinase (FAK)], and NADPH oxidase, to influence downstream pathways. This activation exacerbates inflammatory responses, fibrosis, and pathological cardiovascular remodeling. AT1Rs within the nervous system can also induce excessive activity in the sympathetic nervous system, which increases myocardial strain and facilitates the progression of heart failure. Owing to the importance of AT1R in a variety of diseases, greater demands have been placed on the accuracy of AT1R detection. The structural complexity and low immunogenicity of GPCRs pose considerable challenges in the development of specific antibodies. Many commercially available antibodies for GPCRs, such as those against muscarinic and adrenergic receptors, lack specificity. Current studies on AT1R often use these commercial antibodies, but many fail to demonstrate specificity when AT1R-knockdown or AT1R-overexpressing tissues and cells are tested. This study aims to specifically validate six newly available commercial AT1R antibodies (Supplementary Table S1). Using AT1R global knockout SD rats, cardiomyocyte conditional AT1R knockout C57BL/6N mice, AT1R-overexpressing CHO stable-transformed cell lines and AT1R-overexpressing HEK293 cells, we assessed AT1R expression and localization through receptor-ligand binding assays, RT-PCR, western blot analysis, and immunocytochemistry. Materials and methods are available in Supplementary Materials and Methods. To verify the specificity of the antibody, we generated AT1R-global knockout SD rats (AT1R-KO) using CRISPR-Cas9 technology. Agarose gel electrophoresis revealed bands at approximately 470 bp for AT1R-KO rats and 531 bp for wild-type (WT) rats, confirming successful AT1R knockout at the gene level (Figure 1A). RT-PCR analysis of vascular tissue RNA revealed the absence of AT1R in AT1R-KO rats (Figure 1B). Ligand-receptor binding assays revealed significantly less 125I-Ang II binding to vascular tissue proteins in AT1R-KO rats than in WT rats (Figure 1C). Additionally, primary cardiomyocytes extracted from 0–3-day-old WT and AT1R-KO neonatal rats presented a significant increase in beating rate upon Ang II stimulation in WT rats, whereas no response was observed in AT1R-KO rats (Figure 1D). These results confirmed successful AT1R global knockout in AT1R-KO rats. AT1R-KO rats were thus utilized to verify the specificity of AT1R antibodies (A14201, 25343-1-AP, and 66415-1-Ig). Western blot analysis was conducted on protein extracts from the heart, vascular, liver, and kidney tissues of WT and AT1R-KO rats. Under room temperature denaturation conditions, the A14201 antibody detected AT1R bands at the expected molecular weight (42 kDa) in all tissues from WT rats, the 25343-1-AP antibody detected AT1R in heart and kidney tissues, and the 66415-1-Ig antibody detected AT1R only in the heart tissues. Compared with WT control rats, the A14201 antibody revealed a reduction in AT1R protein expression in AT1R-KO rats.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024126
Transcription factor 3 (TCF3), a pivotal member of the TCF/LEF family, plays a critical role in tumorigenesis. Nonetheless, its impact on the tumor microenvironment (TME) and cancer phenotypes remains elusive. We perform an exhaustive analysis of TCF3 expression, DNA variation profiles, prognostic implications, and associations with the TME and immunological aspects. This study is based on a large-scale pan-cancer cohort, encompassing over 17,000 cancer patients from multiple independent datasets, validated by in vitro assays. Our results show that TCF3/4/7 exhibits differential expression patterns between normal and tumor tissues across pan-cancer analyses. Mutational analysis of TCF3 across diverse cancer types reveals the highest alteration rates in biliary tract cancer. Additionally, mutations and single nucleotide variants in TCF3/4/7 are found to exert varied effects on patient prognosis. Importantly, TCF3 emerges as a robust predictor of survival across all cancer cohorts and among patients receiving immune checkpoint inhibitors. Elevated TCF3 expression is correlated with more aggressive cancer subtypes, as validated by immunohistochemistry and diverse cohort data. Furthermore, TCF3 expression is positively correlated with intratumoral heterogeneity and angiogenesis. In vitro investigations demonstrate that TCF3 is involved in epithelial-mesenchymal transition, migration, invasion, and angiogenesis. These effects are likely mediated through the interaction of TCF3 with the NF-κB/MMP2 pathway, which is modulated by IL-17A in human uveal melanoma MUM2B cells. This study elucidates, for the first time, the significant associations of TCF3 with DNA variation profiles, prognostic outcomes, and the TME in multiple cancer contexts. TCF3 holds promise as a molecular marker for diagnosis and as a potential target for novel therapeutic strategies, particularly in uveal melanoma.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2025101
Abnormal proliferation and migration of endothelial cells are key contributors to tumor angiogenesis. Recent studies have shown that the crucial role of E3 ubiquitin ligase neuronal precursor cell expression developmentally downregulated 4-like (NEDD4L) in tumorigenesis. However, the precise mechanisms by which NEDD4L functions in endothelial cells remain unclear. In this study, we investigate the mechanisms by which NEDD4L influences the function of human umbilical vein endothelial cells (HUVECs) and its effect on tumor angiogenesis. Our results show that NEDD4L overexpression in HUVECs suppresses both cell proliferation and migration. Additionally, we find that the autophagic activity in NEDD4L-overexpressing cells is increased. Proteomic profiling and ubiquitination assays reveal that NEDD4L interacts with eEF1A1, promoting K48-linked ubiquitination-mediated degradation of eEF1A1. This post-translational modification is a key step in the NEDD4L-mediated regulation of autophagy and cellular function. Moreover, we find that loss of endothelial NEDD4L significantly enhances tumor growth and promotes angiogenesis in vivo. Overall, NEDD4L plays a crucial role in inhibiting tumor angiogenesis by regulating eEF1A1 ubiquitination and degradation, providing new insights into the NEDD4L-eEF1A1 axis and its potential as a therapeutic target.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2024026
Adhesion molecules play critical roles in maintaining the structural integrity of the airway epithelium in airways under stress. Previously, we reported that catenin alpha-like 1 (CTNNAL1) is downregulated in an asthma animal model and upregulated at the edge of human bronchial epithelial cells (HBECs) after ozone stress. In this work, we explore the potential role of CTNNAL1 in the structural adhesion of HBECs and its possible mechanism. We construct a CTNNAL1‒/‒ mouse model with CTNNAL1-RNAi recombinant adeno-associated virus (AAV) in the lung and a CTNNAL1-silencing cell line stably transfected with CTNNAL1-siRNA recombinant plasmids. Hematoxylin and eosin (HE) staining reveals that CTNNAL1‒/‒ mice have denuded epithelial cells and structural damage to the airway. Silencing of CTNNAL1 in HBECs inhibits cell proliferation and weakens extracellular matrix adhesion and intercellular adhesion, possibly through the action of the cytoskeleton. We also find that the expressions of the structural adhesion-related molecules E-cadherin, integrin β1, and integrin β4 are significantly decreased in ozone-treated cells than in vector control cells. In addition, our results show that the expression levels of RhoA/ROCK1 are decreased after CTNNAL1 silencing. Treatment with Y27632, a ROCK inhibitor, abolished the expressions of adhesion molecules induced by ozone in CTNNAL1-overexpressing HBECs. Overall, the findings of the present study suggest that CTNNAL1 plays a critical role in maintaining the structural integrity of the airway epithelium under ozone challenge, and is associated with epithelial cytoskeleton dynamics and the expressions of adhesion-related molecules via the RhoA/ROCK1 pathway.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2023285
Cisplatin (CDDP) is a widely used chemotherapeutic agent that has remarkable antineoplastic effects. However, CDDP can cause severe acute kidney injury (AKI), which limits its clinical application. Agrimol B is the main active ingredient found in Agrimonia pilosa Ledeb and has a variety of pharmacological activities. The effect of agrimol B on CDDP-induced renal toxicity has not been determined. To investigate whether agrimol B has a protective effect against CDDP-induced AKI, we first identify Sirtuin 1 (Sirt1) as a critical target protein of agrimol B in regulating AKI through network pharmacology analysis. Subsequently, the AKI mouse model is induced by administering a single dose of CDDP via intraperitoneal injection. By detecting the serum urea nitrogen and creatinine levels, as well as the histopathological changes, we confirm that agrimol B effectively reduces CDDP-induced AKI. In addition, treatment with agrimol B counteracts the increase in renal malondialdehyde level and the decrease in superoxide dismutase (SOD), catalase and glutathione levels induced by CDDP. Moreover, western blot results reveal that agrimol B upregulates the expressions of Sirt1, SOD2, nuclear factor erythroid2-related factor 2, and downstream molecules, including heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1. However, administration of the Sirt1 inhibitor EX527 abolishes the effects of agrimol B. Finally, we establish a tumor-bearing mouse model and find that agrimol B has a synergistic antitumor effect with CDDP. Overall, agrimol B attenuates CDDP-induced AKI by activating the Sirt1/Nrf2 signaling pathway to counteract oxidative stress, suggesting that this compound is a potential therapeutic agent for the treatment of CDDP-induced AKI.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024118
Lung cancer is the leading cause of cancer mortality in China and worldwide, and metastasis is the main cause of patient death. Cancer cells invade and migrate from the primary tumor, enter the circulation system through intravasation, and become circulating tumor cells (CTCs). CTCs that survive in blood vessels extravasate and invade target organs to become disseminated tumor cells (DTCs). DTCs proliferate in target organs to metastasize to distant organs. The previous view was that metastasis is the final stage of cancer progression. Normal cells first transform into tumor cells and then into invasive cancer cells; thus, metastasis occurs. Therefore, the possibility of metastasis is closely related to the size of the primary tumor. This is reflected in the TNM stage (T, tumor size; N, extent of spread to regional lymph nodes; M, metastasis to distant organs), which is often referenced in clinical diagnosis. However, an increasing number of studies are currently challenging this view. A previous study showed that the metastasis of malignant tumors occurs in the early stages of cancer. When patients are diagnosed with primary cancer, dissemination occurs. CTCs already exist in the blood vessels of early-stage lung cancer patients, and in early-stage lung cancer patients, DTCs are likely to be the main source of late-stage metastasis in some cancers; they do not proliferate in target organs, so they cannot be eliminated by surgery, radiotherapy or chemotherapy. As a result, even if the lesions are removed through surgery in these patients, metastasis is still found months or years later, which affects the patient’s quality of life and reduces the patient’s survival period. These observations prompt scientists in the field of metastasis to pay more attention to the prevention and treatment of DTCs when formulating metastasis prevention strategies. To determine whether DTCs exist in different states after entering the target organ, we used a mouse lung cancer metastasis model to generate CTC-TJH-01 cells, which are circulating tumor cells derived from the peripheral blood of early-stage lung adenocarcinoma patients who extravasate into target organs and become DTCs. Then, we observed the distribution and proliferation of DTCs in the lungs. Combined with traditional Chinese medicine theory, our findings can improve clinical medication regimens and promote innovations in metastasis prevention and treatment strategies. We observed the potential distribution and proliferation status of DTCs in the lungs in a mouse lung cancer metastasis model. A lung colonization assay was performed by injecting 5 × 105 CTC-TJH-01 cells into the lateral tail vein of NOD/SCID mice, and vimentin was used as a lung tumor marker. Immunofluorescence staining was performed, and CTC-TJH-01 cells that reached the lungs through the peripheral circulation were evenly spread over 24 h. This finding showed that cancer cells can move to distant sites through the circulation, especially the lungs, which are rich in blood vessels, and stay there in the form of DTCs. However, after 12 weeks, there were only a few visible metastases in the lungs, and many tumor cells in the visible metastases were Ki67-positive. Immunohistochemistry revealed other Vimentin-positive tumor cells in the lungs, but as the number of cells decreased, the Ki67 positivity rate also decreased, and a single tumor cell was negative for Ki67. This finding shows that an unsuitable microenvironment induces DTC apoptosis, and only a very small number of DTCs mediate the formation of an immunosuppressive microenvironment and then proliferate to form metastatic lesions. In addition, DTCs that survive have different proliferation rates; some proliferate to form metastases, while others remain dormant somewhere as individuals. These metastases of different sizes that coexist in the lungs may also have different responses to radiotherapy and chemotherapy due to their different proliferation rates. This may also explain why early-stage lung cancer patients still develop metastasis after standard clinical treatment. Before disseminated tumor cells proliferate and form visible metastases, they generally cannot be detected clinically through conventional diagnostic methods or tumor biomarkers, and patients at this stage often have no clinically significant symptoms; this stage can be called the “metastasis subclinical stage”. Tian et al. proposed the pathogenesis theory of “hidden toxicity due to vital Qi deficiency” for this stage of lung cancer metastasis. According to this theory, DTCs in a dormant state are already present in the metastatic target organs of patients with early-stage lung cancer after surgery. Immunosenescence or stress mediates immune dysfunction, leading to the activation and proliferation of dormant DTCs, which in turn leads to the occurrence of clinical metastasis.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024156
In this study, we aim to investigate diacylglycerol kinase (DGK) γ expression in developing neural tubes (NTs) and its effects on neural stem cell (NSC) proliferation and migration. Whole-mount in situ hybridization (WMISH) and immunohistochemistry are performed to explore DGKγ localization in developing NTs in vivo. NSCs are treated with sh-DGKγ, R59949, or PMA in vitro. Cell counting kit-8 (CCK-8) assay, 5-ethynyl-2′-deoxyuridine (EdU) assay and neurosphere formation assay are utilized to evaluate NSC proliferation. Neurosphere migration assay and a trans-well chamber assay are used to assess NSC migration. The diacylglycerol (DAG) content is detected via enzyme-linked immunosorbent assay (ELISA). The mRNA expression of DGKγ is detected via quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression levels of DGKγ, protein kinase C (PKC) and phosphorylated PKC (p-PKC) are detected via western blot analysis. The results show that DGKγ mRNA is expressed predominantly in developing NTs. The neuroepithelium in developing NTs is positive for NSC markers, including Nestin, glial fibrillary acidic protein (GFAP), and DGKγ. DGKγ is expressed in the cytoplasm and nucleus of the neuroepithelium and is coexpressed with p-PKCγ and p-PKCδ. The proliferation of NSCs, the number of EdU-positive NSCs, and the number of neurospheres are decreased by sh-DGKγ and R59949 but increased by PMA. There is a shorter migration distance of NSCs and fewer migrated NSCs in the sh-DGKγ, R59949 and PMA groups. DAG content and the p-PKCδ/PKCδ ratio are increased by sh-DGKγ, R59949 and PMA, whereas the p-PKCγ/PKCγ ratio is decreased by PMA. Taken together, our findings indicate that DGKγ facilitates NSC proliferation and migration, which is responsible for the participation of DGK in NT development. DGKγ facilitates NSC migration via the DAG/PKCδ pathway.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2024146
Eukaryotic gene expression is regulated at multiple levels, aiding in maintaining normal phenotypes and environmental adaptability. Transcriptional regulation complexity has been extensively studied using high-throughput sequencing, and previous studies have shown that different transcript isoforms can be produced through complex regulatory mechanisms via large-scale RNA sequencing. Additionally, translational regulation, which significantly influences gene expression, is controlled by complex mechanisms [1]. The untranslated regions (UTRs) of eukaryotic mRNA, encompassing the 5′ UTR, 3′ UTR and polyadenylation tail (polyA), are pivotal for translational regulation, with distinct cis-regulatory elements in the 5′ UTR and 3′ UTR of various transcript isoforms, leading to substantial variations in translational regulation across transcripts. To shed light on translational regulation, previous studies have performed isolation of ribosome-associated poly-adenylated RNAs (i.e., translatome) and deep sequencing for mRNA translation [2]. Polysome profiling is the most common method used to study translatome, which can enable the isolation of full-length translated mRNAs, thereby facilitating the identification of UTRs, assessment of selective translation, and comprehension of the regulatory mechanisms underlying gene expression [2]. Drosophila embryonic development progresses very rapidly and requires precise regulation of the transcription and translation of a large number of genes to ensure normal gene expression. Although Drosophila has been extensively studied as a model organism, the specific interplay between transcription and translation during embryonic development stages is not yet fully understood. To investigate the dynamic regulation of gene expression during Drosophila embryogenesis, we conducted transcriptome and translatome co-profiling on early (0‒4 h) embryos and S2R+ cells, a cell line derived from late embryonic stages of Drosophila melanogaster [3], to compare the differences in translational regulation at the gene and transcript isoform levels. S2R+ cell culture and early (0–4 h) embryo collection were performed (see Supplementary Methods) to compare transcriptome and translatome profiling, as shown in Supplementary Figure S1. Cytosolic RNA and ribosome-associated RNA were isolated from embryos [4] and S2R+ cells, which were used for constructing RNA-Seq libraries. Four libraries were generated for RNA-seq (see Supplementary Methods), consisting of two cytosolic RNA libraries and two ribosome-associated RNA libraries (Supplementary Figure S1A,B). The strand-specific RNA-seq libraries were prepared using the Illumina TruSeq Stranded mRNA Sample Preparation Kit (Illumina, San Diego, USA). The library was sequenced on the Illumina HiSeq X Ten System. We employed Trimmomatic [5] to remove low-quality reads, which resulted in approximately 89 million, 76 million, 72 million, and 56 million clean reads for the transcriptome and translatome of the early embryos and S2R+ cells, respectively. These reads were then mapped to the Drosophila genome (UCSC dm6) using HISAT2 [6]. The unique mapped reads ratio ranges from 94% to 85% and reads mapped to rRNA were less than 6% (Supplementary Table S1), indicating the high quality of the four RNA-seq libraries. Using StringTie [7], 33,470 transcripts were assembled for four mapping sequencing libraries, which revealed an average of 1.9 transcribed transcripts and 1.8 translated transcripts per gene (Supplementary Table S1), suggesting the usage of transcript isoforms widely existed in both transcription and translation of Drosophila embryos. To explore the divergence of the transcriptome during Drosophila development, we compared the transcriptome of the early embryos and S2R+ cells to identify genes with |log2(fold change)| ≥1, FPKM ≥1 in at least one condition, and adjusted P value ≤0.001. In total, we identified 2267 differentially expressed genes (DEGs) from 8815 genes. Among these DEGs, 2147 genes showed higher expression levels in the embryos, while 120 genes showed higher expression levels in S2R+ cells (Figure 1A and Supplementary Figure S2A). To investigate the underlying functional mechanism, we performed enrichment analysis to identify DEG-enriched pathways (Supplementary Table S2). Interestingly, the top 10 enriched pathways are related to morphogenesis an
Chinese Traditional and Herbal Drugs•2026•DOI: 10.7501/j.issn.0253-2670.2026.16.20261614
Aging-related sarcopenia remains a clinical challenge due to limited effective interventions. This study systematically evaluated the therapeutic potential of the iridoid fraction from Morinda officinalis and elucidated its mechanism via the PI3K/Akt/mTOR pathway. Using monotropein and deacetylasperulosidic acid as markers, extraction was optimized with 60% ethanol under heated reflux, yielding the highest iridoid content. Purification employed H103 macroporous resin with water as eluent, achieving maximal recovery. In vitro, the fraction significantly ameliorated D-galactose-induced C2C12 myotube atrophy (P < 0.001) and promoted myotube differentiation (P < 0.05, 0.01, 0.001), as evidenced by MYHC expression. In vivo, D-galactose-accelerated aging mice treated with the fraction exhibited increased limb grip strength and hindlimb muscle mass-to-body weight ratio (P < 0.05, 0.01, 0.001), along with expanded cross-sectional area of tibialis anterior and gastrocnemius muscles (P < 0.01, 0.001). Transcriptomic and network pharmacology analyses implicated the PI3K/Akt pathway. Western blotting and qRT-PCR confirmed upregulation of key proteins and genes (PIK3CA, AKT1, mTOR) in the pathway (P < 0.05, 0.01, 0.001), while the PI3K inhibitor LY294002 reversed these effects (P < 0.05). These findings demonstrate that the iridoid fraction from M. officinalis mitigates aging-related sarcopenia through PI3K/Akt/mTOR signaling, providing a promising candidate for clinical translation.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026055
Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer’s disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Atractylodes macrocephala Koidz., exhibits multimodal bioactivities with demonstrated anti-inflammatory and neuroprotective properties. To explore its therapeutic potential against AD pathology, we use high-fat diet (HFD)-fed ApoE knockout (ApoE–/–) mice treated with or without AI for 12 weeks. Integrated bioinformatics analyses and experimental validation reveal that AI treatment markedly attenuates systemic lipid dyshomeostasis, particularly cerebral lipid deposition, suppresses neuroinflammation via downregulation of M1 macrophage polarization markers, and restores cognitive function through neuronal preservation in hippocampal regions. Mechanistically, AI orchestrates cholesterol efflux by upregulating ATP-binding cassette transporter A1 (ABCA1) and liver X receptor (LXR) expression, while concurrently modulating the abundance of arginine biosynthesis metabolites (urea, malic acid, and creatinine) to rebalance neurovascular homeostasis. Notably, western blot and RT-qPCR analyses reveal that AI differentially regulates key enzymes including arginase 1 (ARG1) and simultaneously upregulates the expression of neuronal nitric oxide synthase (nNOS). Further molecular docking and surface plasmon resonance (SPR) analyses confirm the direct binding of AI to ARG1, indicating a novel neuroprotective mechanism involving the modulation of arginine metabolism. These findings delineate the pleiotropic effects of AI against AD pathology and establish a preclinical foundation for the development of AI-based therapeutics targeting neurodegenerative-cardiovascular comorbidities.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21265
BACKGROUND: In recent years, the interdisciplinary application potential of patch-clamp technique in traditional Chinese medicine research has gradually emerged, but a systematic summary of its applications in this field has not yet been conducted. OBJECTIVE: To visualize the application of patch-clamp technology in traditional Chinese medicine field through CiteSpace knowledge map analysis, and to reveal the progress and trends of this technology in the modernization research of traditional Chinese medicine. METHODS: The literature sources included CNKI, VIP, WanFang, PubMed and Web of Science Core Collection database. The computer-assisted literature search was conducted to build a database of patch-clamp technology applications in traditional Chinese medicine field from database inception to September 2024. The authors, institutions, and keywords were subjected to visual analysis and knowledge map drawing using CiteSpace 6.3.R1 software and bibliometric methods. RESULTS AND CONCLUSION: (1) A total of 819 articles were included, with 968 authors. The First Affiliated Hospital of Henan University of Chinese Medicine was the institution with the most publications in the Chinese database, while Harbin Medical University was the institution with the most publications in the English database. (2) The research directions, keyword clustering, and emergence analysis of each institution showed that the application of patch-clamp technique in traditional Chinese medicine mainly focused on cardiovascular electrophysiology, pharmacology of Chinese materia medica, and nervous system electrophysiology. (3) The development of patch-clamp technique in traditional Chinese medicine generally presented an evolutionary path of 'basic mechanism → target deepening → clinical translation', reflecting a transformation from a single technical tool to a multidisciplinary intersection platform. (4) It is suggested that the core influence of authors needs further improvement, and cross-regional cooperation among research institutions is insufficient, so cross-regional cooperation should be strengthened. Current research techniques are single and research content is thin; future research should integrate multiple technologies, cross disciplines, enrich research content, and expand research directions, providing evidence support for in-depth exploration of the internal mechanisms of traditional Chinese medicine.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21375
OBJECTIVE: Many studies have shown that non-invasive neuromodulation techniques can effectively improve the symptoms of non-fluent aphasia after stroke. However, the optimal stimulation protocols for these techniques still need to be further verified and explored. This article used a network meta-analysis method to systematically evaluate the effects of different non-invasive neuromodulation techniques on improving the language function of patients with non-fluent aphasia after stroke. METHODS: The CNKI, WanFang, VIP, CBM, PubMed, Cochrane Library, Embase, and Web of Science databases were searched for randomized controlled trials on the treatment of non-fluent aphasia after stroke with non-invasive neuromodulation techniques, with the search deadline of June 1, 2025. The control group received conventional treatment or sham stimulation, while the experimental group received non-invasive neuromodulation techniques in addition to the control treatment. Outcome measures included the Western Aphasia Battery, Chinese Aphasia Battery, and Communicative Abilities in Daily Living Scale. Stata 17.0 software was used for traditional meta-analysis and network meta-analysis, and GRADE was used to evaluate the evidence level of outcome measures. RESULTS: A total of 33 randomized controlled trials involving 10 non-invasive neuromodulation methods were included. (1) Traditional meta-analysis results showed that low-frequency repetitive transcranial magnetic stimulation (rTMS) over the right Broca's area, transcranial direct current stimulation (tDCS) over bilateral Broca's area, and tDCS over the left Broca's area improved Western Aphasia Battery scores (P < 0.001); low-frequency rTMS over the right Broca's area, low-frequency rTMS over the posterior superior temporal gyrus, and low-frequency rTMS over the right Broca's area combined with high-frequency rTMS over the left Broca's area improved Chinese Aphasia Battery scores (P < 0.05); low-frequency rTMS over the right Broca's area, tDCS over bilateral Broca's area, continuous theta burst stimulation over the right Broca's area combined with intermittent theta burst stimulation over the left Broca's area, high-frequency rTMS over the right Broca's area, and low-frequency rTMS over the right Broca's area combined with high-frequency stimulation over the left Broca's area improved Communicative Abilities in Daily Living Scale scores (P < 0.05). (2) Network meta-analysis results showed that low-frequency rTMS over the right Broca's area was more effective in improving Western Aphasia Battery scores [SMD=1.13, 95%CI(0.59, 1.67), P < 0.05] and Chinese Aphasia Battery scores [SMD=4.73, 95%CI(1.28, 8.18), P < 0.05], while tDCS over bilateral Broca's area was more effective in improving Communicative Abilities in Daily Living Scale scores [SMD=1.81, 95%CI(0.51, 2.12), P < 0.05]. (3) GRADE evidence level evaluation showed that the evidence levels for Western Aphasia Battery, Chinese Aphasia Battery, and Communicative Abilities in Daily Living Scale outcome measures were all low. CONCLUSION: Different non-invasive neuromodulation techniques can improve the language function of patients with non-fluent aphasia after stroke. Low-frequency rTMS over the right Broca's area has significant efficacy in improving multi-dimensional language function, especially in spontaneous speech coherence, auditory comprehension accuracy, and naming fluency; tDCS over bilateral Broca's area is more focused on improving patients' daily communication ability. However, the results are affected by the quantity and quality of included studies, and the evidence level is low, requiring more high-quality studies for further verification.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21337
BACKGROUND: Myelination deficits are a core feature of white matter injury in preterm infants. In recent years, human umbilical cord mesenchymal stem cells have been applied in various animal models of brain injury, demonstrating the capacity to promote myelin repair. Elucidating the regulatory mechanisms by which human umbilical cord mesenchymal stem cells enhance neural myelination will contribute to optimizing therapeutic strategies and facilitating clinical translation. OBJECTIVE: To clarify the reparative effect of human umbilical cord mesenchymal stem cells on myelination disorders caused by maturation arrest of the oligodendrocyte lineage in neonatal rats with white matter injury. METHODS: Seventy-two 2-day-old Sprague-Dawley rats were randomly divided into sham operation group, white matter injury group, and human umbilical cord mesenchymal stem cell transplantation group (n=24 per group). A neonatal rat model of white matter injury was established by combining low-dose lipopolysaccharide with hypoxia-ischemia. On day 14 after modeling, pathological changes in white matter were observed by hematoxylin-eosin staining; the positive expression, protein and mRNA levels of oligodendrocyte lineage transcription factor 2, neural/glial antigen 2, and myelin basic protein were detected by immunohistochemistry, western blot, and real-time quantitative PCR. On day 28 after modeling, myelin formation was observed by Luxol fast blue staining, and spatial learning and memory ability were tested by Morris water maze. RESULTS AND CONCLUSION: On day 14 after modeling, hematoxylin-eosin staining showed that in the white matter injury group, a large number of cells degenerated and necrosed, and nerve fibers were arranged disorderly; in the human umbilical cord mesenchymal stem cell transplantation group, cell morphology was close to normal and nerve fibers were arranged relatively neatly. On day 14 after modeling, there was no statistically significant difference in the positive expression, protein and mRNA levels of oligodendrocyte lineage transcription factor 2 among groups (P > 0.05). Compared with the sham operation group, the positive expression, protein and mRNA levels of neural/glial antigen 2 were upregulated (P < 0.05), while those of myelin basic protein were downregulated (P < 0.05) in the white matter injury group. Compared with the white matter injury group, the positive expression, protein and mRNA levels of neural/glial antigen 2 were downregulated (P < 0.05), while those of myelin basic protein were upregulated (P < 0.05) in the human umbilical cord mesenchymal stem cell transplantation group. On day 28 after modeling, Luxol fast blue staining showed that compared with the sham operation group, myelin expression was decreased in the white matter injury group (P < 0.05); compared with the white matter injury group, myelin expression was increased in the human umbilical cord mesenchymal stem cell transplantation group (P < 0.05). On day 28 after modeling, Morris water maze results showed that compared with the sham operation group, the escape latency was prolonged and the number of platform crossings was decreased in the white matter injury group (P < 0.05); compared with the white matter injury group, the escape latency was shortened and the number of platform crossings was increased in the human umbilical cord mesenchymal stem cell transplantation group (P < 0.05); there was no statistically significant difference in average swimming distance among groups (P > 0.05). These findings indicate that human umbilical cord mesenchymal stem cells can promote the maturation of the oligodendrocyte lineage, repair myelination disorders, and improve cognitive function in neonatal rats with white matter injury.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21477
BACKGROUND: Hernandezine has shown promising therapeutic effects due to its anti-inflammatory bioactivity in diseases such as suppression of tumors, antiplatelet agglutination and diabetes. However, there are no basic studies on the effects and molecular mechanism of Hernandezine on macrophage phenotype and osteoclast activation. OBJECTIVE: To investigate the role of Hernandezine on the regulation of macrophage polarization, osteoclast activation and osteoporosis. METHODS: (1) Cellular experiments: RAW264.7 was used as macrophage model and divided into four groups: Control group, lipopolysaccharide group, lipopolysaccharide + 2.5 μmol/L Hernandezine group, lipopolysaccharide + 5 μmol/L Hernandezine group. Macrophage polarization was induced in the latter three groups using a complete medium supplemented with lipopolysaccharide. The two drug-treated groups received 2.5 and 5 μmol/L Hernandezine, respectively. RAW264.7 cells were induced toward osteoclast differentiation using a complete medium supplemented with nuclear factor κB receptor activator ligand. Macrophage polarization was assessed via qRT-PCR and immunofluorescence for inflammatory cytokine expression. The effects of Hernandezine on osteoclast differentiation were evaluated using qRT-PCR, tartrate-resistant acid phosphatase staining, and F-actin staining. (2) In vivo experiments: Twenty-four female C57BL/6J mice were randomly divided into four groups: sham operation, ovariectomy, ovariectomy + 5 mg/kg Hernandezine, and ovariectomy + 10 mg/kg Hernandezine. The latter three groups underwent bilateral ovariectomy to establish an osteoporosis model. The two drug-treated groups received intraperitoneal injections of Hernandezine at 5 or 10 mg/kg every two days post-surgery. After 8 weeks, femurs were collected for Micro-CT scanning, bone parameter analysis, and hematoxylin-eosin staining to evaluate bone loss. RESULTS AND CONCLUSION: Hernandezine inhibited lipopolysaccharide-induced pro-inflammatory gene expression in macrophages by downregulating the transcription of Toll-like receptor 4/nuclear factor κB signaling pathway-related genes, exhibiting a concentration-dependent effect, with 5 μmol/L showing more significant inhibition. Hernandezine also inhibited the expression of genes related to osteoclast activation and bone resorption, and suppressed osteoclast activation in vitro in a concentration-dependent manner. In vivo, Hernandezine reduced bone loss in estrogen-deficient osteoporotic mice, with the 10 mg/kg group showing better recovery. CONCLUSION: This study confirms that Hernandezine inhibits macrophage pro-inflammatory phenotype transformation and osteoclast activation by downregulating the Toll-like receptor 4/nuclear factor κB signaling pathway, and alleviates excessive bone loss in estrogen-deficient osteoporosis.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21476
BACKGROUND: Recent studies have found that immune cells play an important role in bone metabolism. Myeloid-derived suppressor cells, as a type of immunosuppressive cell, play a significant role in tumor development, but their role in primary osteoporosis remains unclear. OBJECTIVE: To investigate the osteoclastogenic potential of myeloid-derived suppressor cells in naturally aged and ovariectomy-induced osteoporosis mouse models. METHODS: (1) Myeloid-derived suppressor cells and bone marrow-derived macrophages were isolated from 6-8-week-old female C57BL/6 mice. Both cell types were induced for osteoclast differentiation. After 5 days of induction, osteoclast formation was detected by tartrate-resistant acid phosphatase staining. After 3 days of induction, mRNA expression of nuclear factor of activated T-cells 1 and osteoclast-associated immunoglobulin-like receptor was detected by qRT-PCR. (2) 6-8-week-old female C57BL/6 mice (young group, n=6) and 18-month-old female C57BL/6 mice (naturally aged group, n=6) were taken. Bone microstructure of the distal femur was analyzed by Micro-CT. Bone marrow cells were collected from both groups, and the proportion of myeloid-derived suppressor cells was detected by flow cytometry. Myeloid-derived suppressor cells were isolated and induced for osteoclast differentiation. After 5 days of induction, osteoclast formation was detected by tartrate-resistant acid phosphatase staining; after 3 days of induction, mRNA expression of nuclear factor of activated T-cells 1 and osteoclast-associated immunoglobulin-like receptor was detected by qRT-PCR. (3) 6-8-week-old female C57BL/6 mice were randomly divided into sham-operated group (n=6) and ovariectomy group (n=6). Eight weeks after ovariectomy, bone microstructure of the distal femur was analyzed by Micro-CT. Bone marrow cells were collected from both groups, and the proportion of myeloid-derived suppressor cells was detected by flow cytometry. Serum levels of tumor necrosis factor-alpha and interleukin-6 were measured by ELISA. Myeloid-derived suppressor cells were isolated and induced for osteoclast differentiation. After 5 days of induction, osteoclast formation was detected by tartrate-resistant acid phosphatase staining; after 3 days of induction, mRNA expression of nuclear factor of activated T-cells 1 and osteoclast-associated immunoglobulin-like receptor was detected by qRT-PCR. RESULTS AND CONCLUSION: (1) Tartrate-resistant acid phosphatase staining and qRT-PCR showed that the osteoclast differentiation ability of myeloid-derived suppressor cells was stronger than that of bone marrow-derived macrophages. (2) Micro-CT analysis showed that compared with the young group, the naturally aged group had lower bone mineral density, bone volume fraction, and trabecular number (P < 0.05), and increased trabecular separation (P < 0.05). The proportion of myeloid-derived suppressor cells in the naturally aged group was higher than that in the young group (P < 0.05). Tartrate-resistant acid phosphatase staining and qRT-PCR showed that the osteoclast differentiation ability of myeloid-derived suppressor cells in the naturally aged group was stronger than that in the young group. (3) Micro-CT analysis showed that compared with the sham-operated group, the ovariectomy group had lower bone mineral density, bone volume fraction, and trabecular number (P < 0.05), and increased trabecular separation (P < 0.05). The proportion of myeloid-derived suppressor cells and serum levels of tumor necrosis factor-alpha and interleukin-6 in the ovariectomy group were higher than those in the sham-operated group (P < 0.05). Tartrate-resistant acid phosphatase staining and qRT-PCR showed that the osteoclast differentiation ability of myeloid-derived suppressor cells in the ovariectomy group was stronger than that in the sham-operated group. (4) These results indicate that the proportion and osteoclastogenic ability of myeloid-derived suppressor cells increase under conditions of natural aging and estrogen deficiency, which may participate in the occurrence and development of osteoporosis.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21586
BACKGROUND: In recent years, hydrogels have become an important research direction in the treatment of rheumatoid arthritis due to their excellent biocompatibility, controllable drug release performance, and advantages in multiple drug delivery routes. OBJECTIVE: To systematically review the application of hydrogel-based materials as drug delivery carriers in the treatment of rheumatoid arthritis, and explore the impact of different administration routes on the therapeutic effect. METHODS: Using “hydrogel, rheumatoid arthritis, smart hydrogel system, injectable hydrogel, intra-articular injection, transdermal drug delivery” as Chinese and English search terms, we searched PubMed, Web of Science, CNKI, WanFang Data, and VIP. Based on the inclusion criteria, 62 articles were finally included for review. RESULTS AND CONCLUSION: Hydrogels, leveraging their three-dimensional network structures and tunable physicochemical properties, not only allows drugs to accurately reach the lesion area but also significantly prolongs the retention time of drugs in the joint cavity, making them an ideal carrier in the field of drug delivery. The drug release mechanisms of hydrogels mainly include diffusion, chemical regulation, and swelling-mediated release; in addition, stimulus-responsive hydrogels can dynamically regulate drug release behavior based on environmental conditions (such as pH, temperature, enzyme concentration, etc.). In the treatment of rheumatoid arthritis, common administration routes for hydrogel drug delivery systems include parenteral administration, oral administration, transdermal administration, and intra-articular injection, which significantly reduce systemic adverse reactions, improve drug absorption efficiency, and enhance patient compliance. Although hydrogels as drug delivery carriers have shown significant application potential in the treatment of rheumatoid arthritis, long-term safety, biodegradability, and large-scale production still need breakthroughs to promote the clinical translation of hydrogel drug delivery carriers.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21609
BACKGROUND: To further elucidate the etiology and pathogenesis of Parkinson's disease, standardized animal models that more closely mimic clinical conditions have garnered significant attention and achieved notable progress. OBJECTIVE: To review and summarize the current status, development trajectory, and trends in Parkinson's disease animal model research. METHODS: A total of 10 170 relevant literature from two databases, CNKI and Web of Science, were used as data samples. CiteSpace bibliometric software was then used to draw and analyze knowledge graphs of co-occurrence, clustering, emergent terms of keywords, literature publication volume, national/regional publication volume, institutional cooperation network, and literature citation in Parkinson's disease animal model research, followed by analysis. RESULTS AND CONCLUSION: The overall publication volume of Parkinson's disease animal model research, both domestically and internationally, has shown a fluctuating upward trend, with significant growth observed in the Web of Science database. China and the United States were the top publishing countries, accounting for 52.6% of total publications and emerging as primary contributors to research outcomes in this field. The leading domestic institution was Shanghai University of Traditional Chinese Medicine (131 papers), while internationally, Harvard University was the institution with the most publications (263 papers). The distribution of journals and disciplines at home and abroad is concentrated in neuroscience, neurology, molecular biology, traditional Chinese medicine, basic medicine, pharmacology, and other fields. In particular, traditional Chinese medicine treatment of Parkinson's disease has received great attention from domestic scholars, and the potential for interdisciplinary cooperation is huge. Pathological mechanisms related to Parkinson's disease animal models, such as neuroinflammation, gut microbiota, oxidative stress, mitochondrial dysfunction, and α-synuclein, are research hotspots in this field, and ferroptosis has become an emerging theme in domestic research on the mechanism of Parkinson's disease. In terms of treatment of Parkinson's disease symptoms, in addition to the continuous deepening of research on the treatment of Parkinson's disease in traditional Chinese medicine and Western medicine through animal models, new methods such as gene therapy and stem cell transplantation therapy have provided innovative therapeutic strategies in animal model research of Parkinson's disease. With the advancement of the national 'Brain Science Project' and the development of gene editing, artificial intelligence, machine learning, and brain-computer interface technology, these new technologies also have certain exploration space in Parkinson's disease research in the future.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21578
BACKGROUND: Vascular endothelial growth factor receptor 2 is mainly expressed in vascular endothelial cells and plays a crucial role in angiogenesis, tissue repair, and the occurrence and development of diseases. Adeno-associated virus, due to its unique advantages, has been widely applied in mechanism research, disease modeling, and gene therapy fields. OBJECTIVE: To construct an adeno-associated viral vector for vascular endothelial growth factor receptor 2 gene knockdown in rat muscle tissue, determine the knockdown efficiency of vascular endothelial growth factor receptor 2 gene-knockdown adeno-associated virus in the rat sternocleidomastoid muscle and assess its effects on muscle and blood vessels. METHODS: The vector was constructed, and packaged into adeno-associated virus. Following target screening experiments in Sprague-Dawley rats, immunofluorescence assays were conducted to assess viral infection efficiency and vascular endothelial growth factor receptor 2 protein expression. Quantitative real-time PCR was used to measure vascular endothelial growth factor receptor 2 mRNA expression. Ultimately, the optimal shRNA sequences were determined to be Y29478 and the control sequence Y9957. Twelve Sprague-Dawley rats were randomly divided into an adeno-associated virus group and a control adeno-associated virus group for functional verification. The adeno-associated virus was injected into the rat sternocleidomastoid muscle. After 20 weeks, quantitative real-time PCR and western blot were used to detect vascular endothelial growth factor receptor 2 mRNA and protein expression in cervical muscle, hematoxylin-eosin staining was used to detect muscle fiber area, and CD31 immunohistochemistry was used to detect the number of microvessels in cervical muscle. RESULTS AND CONCLUSION: (1) The shRNA sequence and dose that could knock down vascular endothelial growth factor receptor 2 expression were successfully screened, and the knockdown efficiency of vascular endothelial growth factor receptor 2 in rat muscle tissue after in situ injection of vascular endothelial growth factor receptor 2 gene knockdown adeno-associated virus reached 60%. (2) Compared with the control adeno-associated virus group, the mRNA and protein expression of vascular endothelial growth factor receptor 2 in the adeno-associated virus group decreased, the muscle fiber area decreased, and the number of microvessels decreased. (3) A rat model of vascular endothelial growth factor receptor 2 gene knockdown was successfully constructed, and knockdown of vascular endothelial growth factor receptor 2 in muscle tissue caused a reduction in muscle fiber area and a decrease in the number of microvessels.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21580
BACKGROUND: Angiogenesis is one of the critical issues in chronic ulcer healing. Previous studies have indicated that Zizhu ointment can increase the expression of vascular endothelial growth factor in wounds, promote wound healing, and stimulate angiogenesis in high-glucose and high-lipid cell models. OBJECTIVE: To investigate the effects of Zizhu ointment on angiogenesis in diabetic ulcer model mice and elucidate its underlying mechanisms in promoting wound healing. METHODS: Twenty-four mice were randomly divided into four groups: normal control, model control, saline-treated, and Zizhu ointment groups. The diabetic mouse model was established in the latter three groups through a high-fat diet combined with streptozotocin injections. After blood glucose stabilization, full-thickness dorsal skin was removed to simulate diabetic ulcers, with regular monitoring of body mass and blood glucose levels. In the Zizhu ointment group, wound dressings were changed daily. Wound conditions were documented on days 3, 7, 11, and 14. Skin samples were collected after 14 days. Hematoxylin-eosin and Masson staining were used to assess wound healing status. Immunofluorescence staining for vascular endothelial growth factor A (VEGFA) and CD34 was performed to evaluate angiogenesis. Quantitative real-time PCR and western blot analysis were used to detect the expression of angiogenesis-related genes and proteins, including VEGFA, angiopoietin-2 (ANGPT2), sprouty-related EVH1 domain-containing protein 1 (SPRED1), and phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2). RESULTS AND CONCLUSION: The diabetic ulcer model was successfully established. Ulcer healing was delayed in the model group, while the Zizhu ointment group showed significantly faster healing at days 3, 7, 11, and 14 compared with the model group, and at days 7, 11, and 14 compared with the saline group (P < 0.01). Histological staining revealed increased inflammation, reduced hair follicles, and decreased neovascularization in the model group compared with the normal group; the Zizhu ointment group showed increased appendages and neovascularization. Immunofluorescence staining showed reduced positive cells for CD34 and VEGFA in the model group, which were increased after Zizhu ointment treatment. The mean microvessel density in the Zizhu ointment group was higher than that in the model and saline groups (P < 0.05). Gene and protein expression of VEGFA and ANGPT2 were decreased in the model group compared with the normal group (P < 0.01), while SPRED1 and PIK3R2 were significantly increased (P < 0.001). Compared with the model group, the Zizhu ointment group showed significantly increased expression of VEGFA and ANGPT2 (P < 0.05) and decreased expression of SPRED1 and PIK3R2 (P < 0.05), with similar differences compared with the saline group (P < 0.05 or P < 0.01). These findings indicate that streptozotocin-induced diabetic ulcer model mice exhibit delayed ulcer healing and reduced neovascularization. Zizhu ointment treatment accelerates ulcer healing, promotes angiogenesis, and regulates the expression of angiogenesis-related genes and proteins. Thus, topical application of Zizhu ointment may promote diabetic ulcer healing, possibly by modulating wound angiogenesis.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026035
Pulmonary fibrosis (PF) is a life-threatening interstitial lung disease characterized by scarring and inflammation in lung tissues. Aberrant activation of the JAK/STAT and NF-κB signaling pathways is critical in initiating and sustaining the inflammatory processes that drive fibrotic progression. In this study, we identify a novel small-molecule compound, T4015, a 4-indolyl-2-phenylaminopyrimidine derivative, as a dual-pathway inhibitor targeting both JAK/STAT and NF-κB signaling. Dual-luciferase reporter assays demonstrate the potent inhibitory activity of T4015 against these pathways. T4015 effectively suppresses the phosphorylation of STAT3, JAK1, and TYK2 induced by IL-6 and IFN-β, while suppressing LPS-induced NF-κB activation in macrophages. Transcriptome sequencing and pathway enrichment analyses further confirm that T4015 downregulates multiple inflammation-related signaling cascades, including the JAK/STAT, NF-κB, TNF, IL-17, and Toll-like receptor pathways. In a mouse model of bleomycin-induced PF, T4015 treatment significantly improves survival, attenuates collagen deposition, and reduces the expression of pro-inflammatory and profibrotic markers such as IL-6, CCL2, and COL1. Molecular docking and target prediction analyses suggest that T4015 exhibits strong binding affinity for multiple kinases within the JAK/STAT and NF-κB networks, including JAK1, TYK2, JAK2, JAK3, RIPK1, IRAK1/4, TAB1, and ZAP70. Collectively, these results highlight T4015 as a promising therapeutic candidate for PF through its simultaneous inhibition of the JAK/STAT and NF-κB signaling pathways.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026082
E74-like ETS transcription factor 3 (ELF3) has been implicated in various tumorigenesis and inflammatory diseases. However, its expression profile and role in lung adenocarcinoma (LUAD) remain poorly defined. In the present study, through comprehensive clinical and experimental analyses, we aim to clarify the association between ELF3 overexpression in LUAD tissues and poor prognosis. Functional assays reveal that ELF3 knockdown inhibits the proliferation, migration, and invasion of LUAD cells, while ELF3 overexpression enhances these functions. Pathway enrichment analysis indicates that ELF3 influences the metabolic processes of LUAD. Mechanistically, ELF3 exerts oncogenic effects by regulating the transcription of hexokinase 2 (HK2) and glucose transporter type 1 (GLUT1). High-throughput screening reveals that dacinostat, by targeting the active site of the ELF3 protein, attenuates the glycolytic, proliferative, and metastatic abilities of LUAD cells. Additionally, ubiquitin-specific peptidase 18 (USP18) strengthens the stability of the ELF3 protein and influences the malignant biological behavior of LUAD through ELF3. In conclusion, the USP18/ELF3/HK2 and USP18/ELF3/GLUT1 axes play critical roles in glucose metabolism, proliferation, and metastasis of LUAD cells. Dacinostat inhibits the malignant progression of LUAD by targeting ELF3, providing strong evidence for developing novel therapeutic strategies targeting ELF3.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025042
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, with late-stage 5-year survival rates below 50%. Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) drive progression, yet the molecular mediators of CAF-tumor crosstalk are incompletely defined. This study identifies platelet-derived growth factor C (PDGFC) as a critical CAF-secreted factor that promotes epithelial-mesenchymal transition (EMT) and immunosuppression in LUAD. Analysis of patient specimens revealed elevated PDGFC expression in CAFs relative to nontumor tissue fibroblasts (NFs), and high PDGFC levels correlated with poor prognosis. Mechanistically, CAF-derived PDGFC activates the PDGF receptor A (PDGFRA)-mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway in cancer cells, inducing EMT and matrix metalloproteinase 2 (MMP2) expression. PDGFC also stimulates PDGFRA expression in both tumor cells and fibroblasts, establishing a reciprocal positive feedback loop that accelerates fibrotic TME remodeling and malignant progression. Immunologically, PDGFC promotes infiltration and polarization of immunosuppressive cell populations, including CD4+ Treg cells, M2 macrophages, and N2 neutrophils, while restraining immunocompetent NK cells. Immunoinhibitors TGFB1, CSF1R, PD-L1, PD-L2, KDR, IL10RB, and HAVCR2 may synergize with PDGFC in modulating immunosuppression. These findings position PDGFC as a diagnostic indicator and potential immunotherapy target for LUAD, offering a novel TME-targeted therapeutic strategy.
Chinese Journal of New Drugs•2025•DOI: cast_zgxyzz_1236731785313317742
Background: Heart failure with recovered ejection fraction (HFrecEF) is a distinct phenotype with unclear clinical characteristics and prognosis. Methods: We prospectively enrolled 1,234 patients with heart failure and reduced ejection fraction (HFrEF) from January 2015 to December 2018. After optimal medical therapy, 312 patients (25.3%) achieved recovery of left ventricular ejection fraction (LVEF) to ≥50% and were classified as HFrecEF. Clinical characteristics, medication use, and outcomes were compared with those who remained HFrEF. The primary outcome was a composite of all-cause death and heart failure hospitalization. Results: Compared with HFrEF patients, HFrecEF patients were younger, more likely to be female, had a higher prevalence of hypertension and atrial fibrillation, and had a shorter duration of heart failure. They had lower baseline levels of NT-proBNP and smaller left ventricular dimensions. Over a median follow-up of 3.2 years, HFrecEF patients had a significantly lower risk of the primary outcome (adjusted HR 0.45, 95% CI 0.32-0.63, p<0.001). However, 23.4% of HFrecEF patients experienced deterioration of LVEF during follow-up, and these patients had a worse prognosis compared with those who maintained recovery. Independent predictors of LVEF deterioration included ischemic etiology, diabetes, and non-adherence to guideline-directed medical therapy. Conclusions: HFrecEF is associated with a better prognosis than HFrEF, but a substantial proportion of patients may experience LVEF deterioration. Continued optimization of medical therapy and close monitoring are essential for this population.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025023
Heart failure is the terminal stage of multiple cardiovascular diseases, and its incidence is exacerbated by circadian rhythm disturbances. Autophagy, a critical cellular maintenance process, exhibits circadian oscillations, with adverse cardiac events clustering in the early morning when autophagic activity is low. β1-adrenergic receptor autoantibodies (β1-AAs) are present in 40–60% of heart failure patients and persistently activate β1-adrenergic receptors. Prior work confirmed that β1-AAs inhibit myocardial autophagy, but the mechanistic link to circadian rhythm disruption remained undefined. This study demonstrates that β1-AAs disrupt the autophagy rhythm in cardiomyocytes, evidenced by decreased expression of the autophagy marker LC3. β1-AAs also disrupt the rhythmic expression of PER2, a core clock protein, primarily through reduced PER2 protein levels. Metoprolol pretreatment confirmed β1-adrenergic receptor involvement in the β1-AA-induced PER2 reduction. Lentiviral knockdown of Per2 attenuated the β1-AA-induced suppression of LC3, whereas Per2 overexpression significantly restored LC3 expression. mTORC1 activation was identified as a downstream mediator: β1-AAs increased P-mTOR and P-S6 levels at CT8, and rapamycin reversed the LC3II decrease. Per2 downregulation augmented β1-AA-induced P-S6 elevation, while Per2 overexpression reversed it. These findings establish that β1-AA-induced PER2 downregulation promotes mTORC1 activation, inhibiting autophagy and disturbing its circadian rhythm. Targeting PER2 may offer a therapeutic strategy for cardiovascular diseases from a chronobiological perspective.