Gasdermin D in pyroptosis.

Reactive oxygen species (ROS) have been considered the pivotal signaling molecules in many physiological processes, and are usually overproduced in various inflammatory tissues. Overproduction of ROS may disrupt cellular homeostasis, cause non-specific damage to critical components, and lead to a series of diseases. ROS are acknowledged as a type of emerging triggered event similar to acidic pH, overproduced enzymes, temperature and other specific stimuli found in pathological microenvironments. Recently, ROS-responsive biomaterials have been identified as a type of promising therapeutic substance to alleviate oxidative stress in tissue microenvironments, and for use as a vehicle triggered by inflammatory diseases to realize drug release under physiological oxidative microenvironments. In this review, we discuss mainly the mechanisms of ROS-responsive biomaterials with solubility switch and chemical degradation, and those ROS-responsive groups used in ROS-responsive biomaterials. The mechanism of ROS overproduction in pathophysiological conditions is introduced. The various applications of ROS-responsive biomaterials in tissue regeneration and disease therapy, such as cardiovascular diseases, osteoarthritis, chronic diabetic wounds, inflammatory bowel disease and other inflammatory diseases, are summarized.

Reactive oxygen species (ROS)-responsive biomaterials mediate tissue microenvironments and tissue regeneration

Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis

In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is mediated by impairing or bypassing apoptotic cell death. Several novel types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, have recently been reported to play significant roles in the modulation of cancer progression and are considered a promising strategy for cancer treatment. Thus, the switch between apoptosis and pyroptosis is also discussed. Cancer immunotherapy has gained increasing attention due to breakthroughs in immune checkpoint inhibitors; moreover, ferroptosis, necroptosis, and pyroptosis are highly correlated with the modulation of immunity in the tumor microenvironment. Compared with necroptosis and ferroptosis, pyroptosis is the primary mechanism for host defense and is crucial for bridging innate and adaptive immunity. Furthermore, recent evidence has demonstrated that pyroptosis exerts benefits on cancer immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T). Hence, in this review, we elucidate the role of pyroptosis in cancer progression and the modulation of immunity. We also summarize the potential small molecules and nanomaterials that target pyroptotic cell death mechanisms and their therapeutic effects on cancer.

Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment.

Chemotherapy drug-induced nephrotoxicity limits clinical applications for treating cancers. Pyroptosis, a newly discovered programmed cell death, was recently reported to be associated with kidney diseases. However, the role of pyroptosis in chemotherapeutic drug-induced nephrotoxicity has not been fully clarified. Herein, we demonstrate that the chemotherapeutic drug cisplatin or doxorubicin, induces the cleavage of gasdermin E (GSDME) in cultured human renal tubular epithelial cells, in a time- and concentration-dependent manner. Morphologically, cisplatin- or doxorubicin-treated renal tubular epithelial cells exhibit large bubbles emerging from the cell membrane. Furthermore, activation of caspase 3, not caspase 9, is associated with GSDME cleavage in cisplatin- or doxorubicin-treated renal tubular epithelial cells. Meanwhile, silencing GSDME alleviates cisplatin- or doxorubicin-induced HK-2 cell pyroptosis by increasing cell viability and decreasing LDH release. In addition, treatment with Ac-DMLD-CMK, a polypeptide targeting mouse caspase 3-Gsdme signaling, inhibits caspase 3 and Gsdme activation, alleviates the deterioration of kidney function, attenuates renal tubular epithelial cell injury, and reduces inflammatory cytokine secretion in vivo. Specifically, GSDME cleavage depends on ERK and JNK signaling. NAC, a reactive oxygen species (ROS) inhibitor, reduces GSDME cleavage through JNK signaling in human renal tubular epithelial cells. Thus, we speculate that renal tubular epithelial cell pyroptosis induced by chemotherapy drugs is mediated by ROS-JNK-caspase 3-GSDME signaling, implying that therapies targeting GSDME may prove efficacious in overcoming chemotherapeutic drug-induced nephrotoxicity.

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Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity

Aims: Pulmonary fibrosis (PF) is characterized by myofibroblast activation through oxidative stress. However, the precise regulation of myofibroblast transdifferentiation remains largely u...

Tanshinone IIA Activates Nuclear Factor-Erythroid 2-Related Factor 2 to Restrain Pulmonary Fibrosis via Regulation of Redox Homeostasis and Glutaminolysis

Pulmonary fibrosis (PF) is characterized by myofibroblast activation, which can be triggered by oxidative stress. In this study, we investigated the antifibrotic effect of the ethyl acetate extract...

Salvia miltiorrhiza Restrains Reactive Oxygen Species-Associated Pulmonary Fibrosis via Targeting Nrf2-Nox4 Redox Balance.

Uric acid nephropathy (UAN) is caused by excessive uric acid, which results in the damage of renal tissue via urate crystals deposition in the kidneys. The roots and rhizomes of Salvia miltiorrhiza Bunge (S. miltiorrhiza) have been clinically used in many prescriptions to treat uric acid-induced renal damage. This study investigates the uricosuric and nephroprotective effects of the ethyl acetate extract of S. miltiorrhiza (EASM) and tanshinone IIA (a major component of S. miltiorrhiza, Tan-IIA) on UAN and explores the underlying molecular mechanism. Both EASM and Tan-IIA significantly decreased serum uric acid (SUA), serum creatinine (SCR), urine uric acid (UUA), and increased urine creatinine (UCR), and blood urea nitrogen (BUN) levels in experimental UAN mice. In adenine and potassium oxonate-induced mice, EASM and Tan-IIA treatment alleviated renal dysfunction and downregulated the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Moreover, EASM treatment significantly prevented excessive reactive oxygen species (ROS) production in uric acid-induced HK-2 cells and suppressed the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). EASM also suppressed ROS-activated mitogen-activated protein kinases (MAPKs) in vivo and in vitro. These results suggest that both EASM and Tan-IIA demonstrated inhibitory effects on UAN through relieving NOX4-mediated oxidative stress and suppressing MAPK pathways activation.

Lipophilic Extract and Tanshinone IIA Derived from Salvia miltiorrhiza Attenuate Uric Acid Nephropathy through Suppressing Oxidative Stress-Activated MAPK Pathways.

Salviae miltiorrhizae radix et rhizoma is a traditional herbal medicine with anti-cancer activities. In this work, a trace peak enrichment approach combined with a cell proliferation assay was applied for screening cancer cell proliferation inhibitors from the extract of S. miltiorrhiza. A set of 123 peak fractions were prepared, and by comprehensive screening, 21 tanshinones were screened out as cancer cell proliferation inhibitors and their structures were tentatively identified by liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis. The inhibitory activities of nine available screened tanshinones were validated, with their IC50 values ranging from 0.63 to 28.40 μM, indicating their activities strongly inhibit the proliferation of cancer cells. This study presents tanshinones that are potential cancer cell proliferation inhibitors and may explain the anti-cancer activity of S. miltiorrhiza.

Xiao-Wei Zhang

Papers

Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis

Tanshinone IIA Activates Nuclear Factor-Erythroid 2-Related Factor 2 to Restrain Pulmonary Fibrosis via Regulation of Redox Homeostasis and Glutaminolysis

Salvia miltiorrhiza Restrains Reactive Oxygen Species-Associated Pulmonary Fibrosis via Targeting Nrf2-Nox4 Redox Balance.

Lipophilic Extract and Tanshinone IIA Derived from Salvia miltiorrhiza Attenuate Uric Acid Nephropathy through Suppressing Oxidative Stress-Activated MAPK Pathways.

Discovery of cancer cell proliferation inhibitors from Salviae miltiorrhizae radix et rhizoma by a trace peak enrichment approach.