Journal of Cellular Physiology最新文献

As an anthracycline chemotherapy drug, doxorubicin (Dox) is generally prescribed to treat a variety of malignant tumors. Nevertheless, Dox exhibited toxicity at a high dosage, which might eventually lead to injury of the body. Mitochondrial dynamics, including mitochondrial fission and fusion, regulates mitochondrial homeostasis and cellular function. Mounting evidence has demonstrated that imbalance in mitochondrial dynamics, manifested by increased mitochondrial fission or decreased mitochondrial fusion, is associated with the development of Dox-induced diseases. In this paper, we will elaborate the role of mitochondrial dynamics in Dox-induced diseases, and discuss the regulatory mechanism of mitochondrial dynamics in Dox-induced diseases, including apoptosis, fibrosis, myocardial atrophy and inflammation. Elucidating these issues may provide important value in the diagnosis and potential therapeutic strategies for Dox-induced diseases through regulation of mitochondria dynamics.

Products encoded by approximately 30% of the mammalian genome exit the endoplasmic reticulum via the coat complex II (COPII) system en route to their functional destination. Among these cargoes, APOB-containing lipoproteins stand out as abundant and bulky secretory particles with profound implications for human health and diseases. Recent insights into the specialized intracellular itinerary of lipoprotein metabolism and transport not only shed light on longstanding questions of lipid dynamics, but also highlight challenges faced by the COPII machinery in accommodating these complex, unconventional cargoes. Emerging evidence supports that tightly-regulated COPII condensation enables maximal capacity of cargo transport, providing a potential solution tailored for efficient lipoprotein delivery without affecting general protein secretion. This distinction suggests that targeting COPII condensation may provide new therapeutic strategies for lipid-associated diseases. Indeed, recent studies have identified manganese as a key modulator of this process, offering novel insights into its physiological relevance and potential translations.

Sodium/glucose cotransporter 2 inhibitors (SGLT2i) protect against heart failure and fibroinflammation with an unclear mechanistic. Recombinant interleukin-11 (IL11) therapy for thrombocytopenia induces heart failure symptoms and signs. Profibrotic IL11 upregulates extracellular matrix (ECM) proteins, whereas pro-inflammatory tenascin-C (TNC) is an ECM-derived alarmin. We hypothesized IL11 upregulated TNC to induce fibroinflammation via Toll-like receptor 4 (TLR4) and prototype SGLT2i dapagliflozin counteracted the effects. We stimulated fibroblasts with IL11 and confirmed TNC upregulation. NADPH oxidase 2 (NOX2) is known to participate in TNC-TLR4 signaling. We treated IL11-stimulated fibroblasts with inhibitors of TLR4 (TLR4i) and NOX2 (NOX2i) and found IL11 induced an imperative profibrotic TNC-TLR4-NOX2 auto-amplification loop. IL11 is known to induce ERK-dependent positive autofeedback. By finding TLR4i and NOX2i inhibited IL11-induced ERK phosphorylation, we suspected IL11-ERK joined TNC-TLR4-NOX2 auto-amplification fibroinflammatory pathway. We stimulated fibroblasts with TNC and found IL11 upregulation. We treated TNC-stimulated fibroblasts with TLR4i, NOX2i, or neutralizing IL11 antibody and confirmed TLR4-NOX2 and IL11 were indispensable for TNC-induced fibrosis. We concluded that IL11-ERK, TNC-TLR4, and NOX2 are interdependent in fibroblasts and together make a positive-feedback loop to sustain fibroinflammation. We checked mRNA expression of relevant proteins from proteinatlas.org and found fibroblasts are overwhelming producers of IL11 and TNC in the heart. IL11 receptor subunit alpha (IL11RA) and TLR4 are highly differentially expressed with the former on cardiomyocytes and the latter on macrophages. We therefore proposed a model of differentially activated IL11RA and TLR4 signaling in response to mutually reinforcing IL11-TNC alarmins, to explain how activated fibroblasts pivotally support fibroinflammatory microenvironment and how danger signals induce cell-type-specific responses. Next, we showed dapagliflozin prevented fibroinflammation induced by IL11 or TNC. Mechanistically, we showed dapagliflozin antagonized IL11RA by molecular docking, fluorescence quenching, and grading-dose IL11-signaling inhibitor cocktails studies. In conclusion, dapagliflozin interrupts pro-fibroinflammatory IL11-TNC bi-alarmin mutual reinforcement in human cardiac fibroblasts by antagonizing IL11RA.

Osteoarthritis (OA) is increasingly recognized as a chronic inflammatory degenerative joint disease. Recent evidence exhibits a higher prevalence of OA among patients with type II diabetes mellitus (T2DM). Metallothioneins (MTs) are important proteins involved in controlling physiology and pathophysiology. MT-1/MT-2 have been further found their positive correlation with OA progression, but their precise roles need more examination. This study aimed to investigate the role of MT-1/MT-2 in the development of diabetic OA and the underlying mechanisms. Cartilage was collected from patients with OA-only and T2DM-OA, and from rats classified as healthy, T2DM, and T2DM with destabilization of medial meniscus (DMM) surgery. Additionally, a cell model treated with high glucose (HG) or advanced glycation end products (AGEs) was used to investigate underlying mechanisms. Our results revealed that MT-1/MT-2 levels were elevated in cartilage from T2DM-OA patients and rats, as well as in T2DM rats subjected to DMM surgery. Similarly, primary chondrocytes treated with HG and AGE showed increased expression of MT-1/MT-2, with distinct distributions and regulatory mechanisms: (a) MT-1 enhanced MMP and transcription factor activity without affecting their expressions, whereas MT-2 increased both the activity and expression of MMPs and transcription factors; (b) MT-1 reduced IL6/IL8 expression, while MT-2 promoted it. Furthermore, this differential regulation appears to be mediated by BMP2 autocrine stimulation. These findings underscore the dual role of MT-1/MT-2 in simultaneously activating self-repair and degenerative processes, potentially influencing diabetic cartilage pathogenesis. Our study suggests that MT-1/MT-2 may serve as valuable theranostic targets for diabetic OA in future clinical applications.