Journal of Cellular Physiology最新文献

We attempt to address two key therapeutic obstacles affecting glioblastoma patients: low ability of anticancer drugs to penetrate the blood-brain barrier (BBB), and temozolomide (TMZ) resistance, by targeting mitochondrial respiration of glioblastoma cells. We designed and tested over 100 new compounds based on the chemical structure of fenofibrate (FF), which in its prodrug form is cytotoxic to cancer cells by causing severe impairment of mitochondrial respiration. The compounds were designed using two key predictive tools: central nervous system–multiparameter optimization (CNS-MPO) and BBB_SCORE. These algorithms assess how effectively compounds can penetrate the BBB. We initially selected PP1 as a lead compound by testing its BBB penetration, metabolic performance, and antitumoral efficacy. PP1 accumulated in brain tumors and triggered glioblastoma cell death. However, PP1-induced inhibition of mitochondrial respiration was followed by an immediate glycolytic response, which attenuated PP1 toxicity in a glucose-dependent manner. To bypass this limitation, we tested two strategies: (1) the use of PP1 in combination with glycolysis inhibitors; and (2) introduction of a new compound, PP211, which inhibited mitochondrial respiration in the absence of a concomitant increase of glycolysis. Although the combination of PP1 with glycolysis inhibitors was very effective in vitro, this drug combination demonstrated elevated toxicity in mice. PP211, instead, attenuated TMZ-resistant tumor growth and prolonged mouse survival with only minimal general animal toxicity. In summary, we developed and tested a novel mitochondria-targeting drug candidate, PP211, which effectively crosses the BBB, overcomes TMZ resistance, and induces tumor cell death independently of glucose levels—while exhibiting minimal systemic toxicity in preclinical models. These findings support further development of PP211 for glioblastoma therapy.

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.