Molecular Biology Reports最新文献

Hydrogen sulfide (H₂S), once known as a toxic gas, is now acknowledged as a fundamental gasotransmitter essential for ocular homeostasis. This review critically examines the paradoxical role of H₂S in the eye, how it acts as both a vital signaling molecule and a potential pathological contributor depending on concentration, cellular context, and disease stage. We explore the compartmentalized synthesis of H₂S via three principal enzymatic pathways, viz., cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and the 3-mercaptopyruvate sulfurtransferase/cysteine aminotransferase (3MST/CAT) system. Also, it's nuanced signaling through protein persulfidation, ion channel modulation (KATP, Ca²⁺), and transcriptional regulation (Nrf2/ARE, NF-κB, cAMP/cGMP). Dysregulation of H₂S dynamics is implicated in major ocular diseases, including glaucoma, diabetic retinopathy, and retinal degeneration, where it can paradoxically preserve or impair function. A central translational challenge is designing controlled-release H₂S donors (e.g., GYY4137, ACS67) that replicate physiological signaling while overcoming formidable ocular bioavailability barriers. We evaluate advanced delivery platforms, from in situ gels to nanoparticle systems, that promise targeted and sustained release. By integrating molecular mechanisms with a critical appraisal of conflicting evidence, this review establishes a conceptual framework for H₂S-based therapeutics and highlights unresolved mechanistic questions and delivery hurdles that must be addressed to realize clinical potential.

Background: Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy with suboptimal treatment outcomes, necessitating the development of novel therapeutic strategies. Metabolic reprogramming, particularly a dependency on glycolysis, is a hallmark of cancer cells. The cysteine-rich intestinal protein 1 (CRIP1) gene exhibits dual roles in cancer, but its function in AML metabolism remains unexplored. This study investigated the metabolic consequences of CRIP1 knockdown and the subsequent efficacy of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) compared to the oxidative phosphorylation (OXPHOS) inhibitor IACS-010759.

Methods: Stable CRIP1 knockdown (CRIP1-KD) was established in the OCI-AML3 cell line using lentiviral shRNA. Metabolic changes were assessed by measuring glucose consumption and lactate secretion. Expression of lactate dehydrogenase A (LDHA) was evaluated by Western blot. The cytotoxic effects of 2-DG and IACS-010759 were determined via flow cytometry using 7-AAD staining.

Results: CRIP1-KD cells demonstrated an 87% reduction in CRIP1 expression (*p*<0.001) and a significant increase in both glucose uptake (*p*=0.04) and lactate production (*p*=0.01) compared to scramble control (SCR) cells. This glycolytic phenotype was corroborated by a 3.3-fold upregulation in LDHA protein expression. Treatment with 2-DG resulted in a more pronounced suppression of glucose consumption and lactate production than IACS-010759 in CRIP1-KD cells (*p*=0.01). Consequently, CRIP1-KD cells exhibited significantly higher cell death after 2-DG treatment (29.10%) compared to IACS-010759 treatment (17.25%; *p*=0.003).

Conclusion: Our findings indicate that CRIP1 knockdown induces a glycolytic switch in AML cells, rendering them exquisitely sensitive to glycolytic inhibition by 2-DG. This suggests that CRIP1 status could serve as a biomarker for predicting response to metabolic therapies and highlights 2-DG as a promising therapeutic agent for a subset of AML characterized by glycolytic dependency.

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system marked by demyelination, inflammation, and progressive neuronal damage. Current immunotherapies reduce relapse frequency but fail to stop silent progression driven by microglial activation or to promote effective remyelination. Mesenchymal stem cells (MSCs) have shown therapeutic promise; however, their clinical use is restricted by issues of survival, distribution, and large-scale production. Increasing evidence indicates that MSC benefits are primarily mediated by their secretome, especially exosomes, nanosized vesicles that carry proteins, lipids, and nucleic acids that modulate immune activity and enhance neuroregeneration. In preclinical models, MSC-derived exosomes suppress pro-inflammatory microglia, increase anti-inflammatory signaling, and stimulate oligodendrocyte maturation and myelin repair. These vesicles can cross the blood-brain barrier, exhibit low immunogenicity, and function as cell-free therapeutics. Early clinical findings in non-neurological disorders confirm their safety, while intranasal administration offers a practical delivery route. Collectively, these insights highlight exosomes as a promising next-generation therapy capable of addressing both inflammation and neurodegeneration in multiple sclerosis.