Cell Biology and Toxicology最新文献

KRP-203, a novel agonist of sphingosine-1-phosphate receptors (S1PRs), has shown promise in treating in immune-related diseases by blocking lymphocyte recruitment to inflamed tissues. Although S1PRs are abundantly expressed in cardiomyocytes, the specific effects of KRP-203 on these cells remain poorly understood. Here, we investigated the impact and mechanisms of KRP-203 pretreatment on myocardial ischemia-reperfusion injury (MIRI) via its interaction with cardiomyocyte S1PRs. To evaluate the efficacy of KRP-203 administered before ischemia, three MIRI models (in vivo, ex vivo, and in vitro) were employed. Overall, KRP-203 pretreatment significantly improved left ventricular systolic function, lowered serum levels of creatine kinase MB isoenzyme and lactate dehydrogenase, mitigated myocardial histopathological damage, and reduced both infarct size and cardiomyocyte apoptosis in vivo. Similar protective effects were observed in the in vitro and ex vivo models. Additionally, KRP-203 was found to preferentially bind to S1PR1 over S1PR2 and S1PR3 in cardiomyocytes. Further analysis revealed that pretreatment with KRP-203 significantly lowered the concentration of reactive oxygen species (ROS), prevented mitochondrial permeability transition pore opening, boosted mitochondrial membrane potential (MMP), and increased phosphorylation of AKT, EKR, GSK-3β, JAK2, and STAT3. These effects were reversed by S1PR1 knockdown in cardiomyocytes. Moreover, knocking down S1PR1 in the heart abrogated the cardioprotective effects of KRP-203. In summary, the findings indicate that KRP-203 pretreatment alleviates MIRI independently of lymphocyte involvement. Mechanistically, KRP-203 selectively activates S1PR1 on cardiomyocytes, triggering the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways to maintain mitochondrial integrity. These findings provide fresh perspectives on the pharmacological properties of KRP-203.

Kidney disease is increasingly linked to dysregulated lipid metabolism, yet the molecular mechanisms driving renal lipotoxicity remain poorly understood. This review elucidates the pivotal role of the hepatic nuclear factor-1 family (HNF-1α and HNF-1β) in renal lipid homeostasis, integrating clinical and experimental evidence. Functionally, HNF-1 isoforms regulate lipid synthesis, oxidation, and transport via conserved POU domains and transcriptional networks. HNF-1α enhances high-density lipoprotein (HDL)-mediated cholesterol efflux through ApoM, while concurrently regulating PCSK9 to promote LDL receptor (LDLR) endocytosis and degradation, thereby inhibiting cholesterol uptake; whereas, HNF-1β promotes cholesterol synthesis via activation of HMGCR/SREBF2 and modulates the PCSK9-LDLR axis. Additionally, HNF-1β coordinates triglyceride metabolism through farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways, and regulates mitochondrial fatty acid β-oxidation (FAO) via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). Clinically, HNF-1α (MODY3) and HNF-1β (MODY5) mutations are closely associated with dyslipidemia, proteinuria, and CKD progression, with lipotoxicity serving as a key pathogenic driver. Therapeutic strategies targeting HNF-1 include pharmacological agents (e.g., metformin, GLP-1 agonists) and natural compounds (berberine, resveratrol) that modulate its transcriptional activity, alongside CRISPR and miRNA-based precision interventions. This review summarizes the important and multifaceted role of HNF-1 in renal metabolic disorders, highlighting its potential as a therapeutic target and offering new strategies for precision nephrology.

Fatty liver disease, encompassing metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD), is frequently linked to high-calorie diets, excessive alcohol consumption, or other metabolic disorders. These conditions can escalate to cirrhosis and even hepatocellular cancer (HCC), resulting in a substantial economic burden worldwide. Nicotinamide adenine dinucleotide (NAD +) is a coenzyme that plays a critical role in cellular metabolism and homeostasis. Its depletion has been observed in cases of fatty liver disease, while restoration of NAD + levels has been shown to mitigate the initiation and progression of disease. This review presents advances of NAD + in the pathophysiology of fatty liver disease, focusing on the biological roles of NAD + in liver lipid accumulation, oxidative stress, endoplasmic reticulum stress (ERS), inflammation, autophagy, and liver fibrosis during the development of fatty liver disease. Furthermore, the potential of NAD + as a therapeutic target for fatty liver disease is also discussed.

Macrophage M2 polarization plays a pivotal role in breast cancer development. The present study aimed to investigate the interplay of the Leupaxin (LPXN)/HDAC6/EGR2 axis in breast cancer and its impact on macrophage M2 polarization. Our findings indicate that LPXN overexpression in breast cancer tissues correlates with M2 macrophage polarization. To investigate LPXN's potential role, we conducted siRNA-mediated silencing in macrophages. In a breast cancer cell-macrophage co-culture system, LPXN silencing was associated with reduced cancer cell proliferation, decreased M2 polarization markers, and diminished HDAC6 expression. BIOGRD and experimental data suggest a regulatory relationship between LPXN and HDAC6. Notably, HDAC6 inhibition partially reversed the pro-M2 effects of LPXN overexpression. Further mechanistic studies revealed that HDAC6 interacts with EGR2, functioning as its deacetylase and negatively regulating EGR2 expression. EGR2 silencing partially attenuated the anti-M2 effects observed with LPXN knockdown. In murine breast cancer models, LPXN silencing was linked to increased M1 macrophage markers and reduced tumor burden. These findings suggest LPXN may influence breast cancer progression through HDAC6/EGR2-mediated regulation of macrophage polarization. In conclusion, our study demonstrated that the LPXN/HDAC6/EGR2 axis promotes breast cancer progression by augmenting macrophage M2 polarization.

Background: TA-65®, a telomerase-activating compound derived from Astragalus membranaceus, has garnered interest for its potential to modulate cellular aging. However, its mechanistic efficacy and long-term toxicological profile remain inadequately synthesized.

Methods: This PRISMA-guided meta-analysis evaluated 8 randomized controlled trials (RCTs, n = 750 participants; mean age 63.3 years) assessing TA-65's effects on telomere dynamics, functional aging indices, and safety outcomes. Primary outcomes included leukocyte telomere length (LTL) measured by Southern blot or qPCR/or flow-FISH; secondary outcomes encompassed frailty metrics (SPPB, grip strength, 6MWT), inflammatory markers (hs-CRP, IL-6), and adverse events (CTCAE v5.0). Statistical synthesis employed random-effects models (RevMan 5.3), subgroup analyses, and GRADE evidence grading.

Results: TA-65 supplementation induced moderate telomere elongation (SMD = 0.47, 95% CI: 0.31-0.62; p < 0.00001), with amplified effects in adults > 60 years (SMD = 0.63 vs. 0.36; p = 0.03). Industry-funded trials reported inflated efficacy (SMD = 0.63 vs. 0.40; p = 0.03). Critically, telomere elongation did not translate to functional improvements in frailty (SMD = 0.09, p = 0.15) or inflammation (CRP/IL-6 SMD =  - 0.11, p = 0.07), revealing a telomere-function disconnect. Safety analysis (n = 487) identified mild gastrointestinal toxicity (12.4% incidence; nausea: 7.1%, abdominal discomfort: 5.3%) but no severe adverse events (e.g., oncogenesis) over 12 months. Dose-response relationships (10-50 mg/day) and measurement-method variations were non-significant (p > 0.05).

Conclusions: While TA-65 demonstrates telomerase-activating efficacy, particularly in older adults, its failure to improve functional aging metrics underscores limitations of unimodal biomarker targeting. The absence of dose-dependent toxicity or short-term oncogenic risk is notable, yet long-term carcinogenic potential remains unaddressed. Rigorous, independent trials must evaluate TA-65's chronic toxicity, telomere-independent mechanisms, and utility within multidimensional aging frameworks. Clinical application may consider older adults with immunosenescence, incorporating safety surveillance for gastrointestinal and oncological endpoints.

Psychotic disorders frequently result from repeated ketamine exposure, yet the underlying mechanisms remain elusive. We propose that repeated exposure to ketamine may induce psychotic-like behaviors via DRD1-mediated nuclear signaling pathways. Our investigation focused on phosphorylated DARPP-32 at Thr34, Thr75, and Ser97, alongside transcriptome profiling in both cell and mouse models. We found that DRD1 antagonist mitigated ketamine-induced psychotic-like behaviors and cognitive deficits, whereas DRD1 agonist partially replicated ketamine-like symptoms. In cellular models, ketamine elevated p-Thr34 DARPP-32 levels and facilitated its nuclear accumulation through PKA, while promoting Ser10 H3 phosphorylation by inhibiting PP1 activity. Phosphorylation at Thr75 and Thr97 inhibited p-Thr34 level, with Thr97 enhancing DARPP-32 and PP1 interaction. In vivo, combined approach of RNA-seq and ATAC-seq in the hippocampus indicated that ketamine suppressed neurogenesis. Immunofluorescence showed reduced neonatal neurons and neural stem cells in the dentate gyrus region, while ketamine increased astrocyte numbers. Single-nucleus transcriptome sequencing revealed enhanced neuron-astrocyte interaction post-ketamine treatment. In summary, we identified the DRD1-DARPP-32-Histone H3 pathway as a key mediator of transcriptional abnormalities and impaired hippocampal neurogenesis in ketamine-induced psychotic-like mouse model.

Liver fibrosis, a common manifestation in numerous hepatic diseases, is critical in the progression from mild injury to cirrhosis and ultimately to hepatocellular carcinoma. To date, there are no effective pharmacological therapies for liver fibrosis. Ferroptosis is a type of programmed cell death characterized by alterations in redox lipid metabolism and is associated with the pathological conditions in liver fibrosis. The induction of ferroptosis is considered a novel way to kill hepatic stellate cells (HSCs). However, some studies in recent years challenge the existing paradigm. In addition to promoting HSC death, ferroptosis sets in motion the activation of profibrogenic HSCs and causes the death of hepatocytes and immune cells. In this review, we discuss the dual role of ferroptosis in promoting and inhibiting fibrosis in the liver, and the ferroptosis-related mechanisms underlying liver fibrosis of distinct etiologies. Despite significant progress in understanding ferroptosis's pathological roles in liver fibrosis, we highlight several critical questions that need to be addressed for strategies based on ferroptosis-targeted therapies, taking into account its ambiguous role in liver fibrosis.

Background: Atherosclerosis (AS) is a cardiovascular problem, which is featured by the accumulation of lipids in the intimal layer of the arterial wall and inflammatory reaction of immune cells. CCL17 is an inflammatory mediator associated with promoting AS. Nevertheless, the specific role of CCL17 and its upstream regulatory mechanisms in macrophage mediated inflammation and AS remain unclear.

Methods: An AS mice model was established by subjecting ApoE^-/- mice to a high-fat diet (HFD). Constructing an AS cell model by treating primary macrophages with oxidized low-density lipoprotein (ox LDL). Injecting shRNA wrapped by AAV virus into the tail vein of mice knocked down CCL17 and SENP3 in mice. Hematoxylin-eosin (HE) and oil red O staining were used to detect arterial injury in mice. The changes of Treg cells were detected by flow sorting. Cycloheximide (CHX) and immunoprecipitation were used to detect the level of DeSUMOylation of CCL17 modified by SENP3.

Results: The CCL17 and SENP3 expression in plaque sample of AS mice were significantly up-regulated. Knocking down CCL17 or SENP3 in mice could reverse the vascular damage, lipid accumulation, the increase of the blood lipid levels and the increase of inflammatory reaction in AS mice. On the molecular mechanism level, SENP3 increased the protein stability of CCL17 and thus increased CCL17 expression by DeSUMOylation modification at K115 site of CCL17 protein. In macrophages induced by oxLDL, CCL17 and CCL22 affect the chemotaxis of Treg competitively.

Conclusion: This study showed that SENP3 mediated deSUMOylation of CCL17, increase CCL17 expression in macrophage. CCL17 secreted by macrophage regulating Treg recruitment through the competitive interaction between CCL17 and CCL22 and thus aggravated AS. Our findings provide a new regulatory mechanism and potential target for AS treatment.

This study investigates the functions of chromobox 6 (CBX6) in esophageal squamous cell carcinoma (ESCC) and delves into its functional mechanisms. The bioinformatics insights suggested that CBX6 was overexpressed in ESCC and linked to dismal prognosis. Cbx6 knockdown was induced in mouse mEC25 cells. This procedure curbed the proliferation and migration of mEC25 cells and reduced exhaustion of the co-cultured CD8⁺ T cells. In vivo, Cbx6 knockdown in mEC25 cells reduced tumorigenesis while enhancing immune activity in mice. Further experiments showed that CBX6 reduced CD8⁺ T cell cytotoxicity by secreting C-C motif chemokine ligand 8 (CCL8) and promoting monocarboxylate transporter 4 (MCT4)-mediated lactate transport. Regarding the mechanism, CBX6 regulated the expression of SWI/SNF related BAF chromatin remodeling complex subunit D1 (Smarcd1) to modulate chromatin remodeling, thus promoting transcription of Ccl8 and Slc16a3 (encoding MCT4). Smarcd1 overexpression restored metabolic activity in mEC25 cells, reduced activity of co-cultured CD8⁺ T cells, and promoted tumorigenesis in vivo. Tissue microarrays analysis suggested that CBX6 and SMARCD1 were linked to immunosuppression and poor prognosis in clinical samples. In conclusion, this study suggests that CBX6 induces CD8⁺ T cell exhaustion and tumor development in ESCC through SMARCD1-mediated CCL8 secretion and lactate efflux.

Lipolysis, a tightly regulated metabolic process, is hijacked by cancer cells to meet their energy and biosynthetic demands under stress. Central to this process is hormone-sensitive lipase (HSL), a key enzyme that orchestrates lipid mobilization by hydrolyzing diacylglycerols into free fatty acids (FFAs). This review explores the pivotal and multifaceted role of HSL in cancer metabolism, focusing on its dual function acting as both a tumor promoter and suppressor depending on the cancer type and microenvironment. Lipolysis, the breakdown of triglycerides into free fatty acids (FFAs), is essential for maintaining energy homeostasis, and is co-opted by tumor cells to fuel growth. Enzymes such as ATGL, HSL, and MGL synergistically regulate lipolysis, with HSL being the driver in this process. Dysregulation of HSL can either promote or inhibit cancer growth, depending on the tumor type. We examine how deregulated HSL activity contributes to tumor progression, metastasis, and therapy resistance through metabolic reprogramming, particularly in the context of cancer-associated adipocytes (CAAs) and fibroblasts (CAFs). CAAs and CAFs within the tumor microenvironment modulate lipid metabolism, influencing tumor progression. The review also discusses the interplay between HSL and oncogenic signaling pathways, its regulation by hormonal and transcriptional networks, and its impact on immune modulation and cachexia. Finally, we evaluate the therapeutic potential of targeting HSL, emphasizing the need for cancer-type-specific strategies to exploit its vulnerabilities without exacerbating metabolic imbalance. By decoding HSL's role in cancer energetics, this review provides a foundation for novel interventions aimed at disrupting tumor lipid metabolism. Although, therapeutic strategies targeting lipolytic enzymes, such as HSL holds promise, this review also iterates the requisite for context specific considerations for successful application.