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Global climate change‐caused drought stress, high temperatures and other extreme weather profoundly impact plant growth and development, restricting sustainable crop production. To cope with various environmental stimuli, plants can optimize the opening and closing of stomata to balance CO2 uptake for photosynthesis and water loss from leaves. Guard cells perceive and integrate various signals to adjust stomatal pores through turgor pressure regulation. Molecular mechanisms and signaling networks underlying the stomatal movements in response to environmental stresses have been extensively studied and elucidated. This review focuses on the molecular mechanisms of stomatal movements mediated by abscisic acid, light, CO2, reactive oxygen species, pathogens, temperature, and other phytohormones. We discussed the significance of elucidating the integrative mechanisms that regulate stomatal movements in helping design smart crops with enhanced water use efficiency and resilience in a climate‐changing world. [ABSTRACT FROM AUTHOR]

Background/Aims: Sinomenine, a pure alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, and sinomenine hydrochloride (SN) has been successfully used for the therapy of rheumatoid arthritis (RA) and kidney diseases. Autophagy is a cytoprotective mechanism used by podocytes and other cells to alleviate the effects of oxidative stress, and angiotensin II (Ang II) significantly promotes podocyte autophagy. However, excessive autophagy may lead to cell death and podocyte depletion. The present study evaluated the effect of SN in podocytes induced by Ang II. Methods: Podocytes were pretreated with graded concentrations (10-8 M ∼ 10-4 M) of SN and then stimulated with Ang II. The LC3B protein and the p47-phox membrane fraction were measured by Western blot. Autolysosomes were assessed by transmission electron microscopy. FACS was used to quantify the ROS produced by podocytes. The translocation of p47-phox to the membrane was investigated by immunofluorescence. Results: The 10-8 M ∼ 10-4 M of SN alone did not effect ROS generation or podocyte autophagy. The 10-8 M and 10-6 M SN attenuated Ang II-induced autophagy in podocytes. Furthermore, SN decreased the level of ROS generation in Ang II-induced podocytes via inhibition of NOX subunit p47-phox translocation to the membrane. Conclusion: The appropriate concentration of SN attenuated Ang II-induced podocyte autophagy through ROS generation, at least in part, by regulating NOX subunit p47-phox translocation to the membrane. [ABSTRACT FROM AUTHOR]

Intracellular redox imbalance, achieved by exploiting the tumor microenvironment (TME), has emerged as a promising strategy for cancer therapy. In this study, we developed a multifunctional nanoadjuvant, termed GITFe/Z-HA, by modified a metal-organic backbone Fe/ZIF-8 with hyaluronic acid (HA) targeting. The nanocarriers were loaded with glucose oxidase (Gox), neoindocyanine green (IR820) and tilazamine (TPZ). This design aimed to achieve a cascade reaction within tumor cells, mediated by Gox, Fe3+, and IR820, which consumes intrinsic glucose and oxygen, leading to an elevated production of reactive oxygen species (ROS). This cascade reaction creates a hypoxic environment conducive for TPZ to exert its therapeutic action. Consequently, the combination of photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy demonstrates a good synergistic effect. Moreover, the imbalanced ROS/glutathione (GSH) induced by this treatment approach, along with PTT, promote immunogenic cell death (ICD). This ICD triggers the release of damage-related molecular patterns and CD8+ lymphocyte infiltration sensitizes the immune checkpoint blockade (αPD-L1) response, thereby eliciting a systemic anti-tumor immune response. Collectively, this comprehensive treatment regimen, driven by environmentally stimulated multiple pathways, overcomes the limitations of single therapeutic modalities, thereby improving tumor outcomes. Additionally, these findings provide valuable insights for strategies aimed at modulating the tumor immune microenvironment. [Display omitted] [ABSTRACT FROM AUTHOR]

Background/Aims: Sinomenine, a pure alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, and sinomenine hydrochloride (SN) has been successfully used for the therapy of rheumatoid arthritis (RA) and kidney diseases. Autophagy is a cytoprotective mechanism used by podocytes and other cells to alleviate the effects of oxidative stress, and angiotensin II (Ang II) significantly promotes podocyte autophagy. However, excessive autophagy may lead to cell death and podocyte depletion. The present study evaluated the effect of SN in podocytes induced by Ang II. Methods: Podocytes were pretreated with graded concentrations (10-8 M ~ 10-4 M) of SN and then stimulated with Ang II. The LC3B protein and the p47-phox membrane fraction were measured by Western blot. Autolysosomes were assessed by transmission electron microscopy. FACS was used to quantify the ROS produced by podocytes. The translocation of p47-phox to the membrane was investigated by immunofluorescence. Results: The 10-8 M ~ 10-4 M of SN alone did not effect ROS generation or podocyte autophagy. The 10-8 M and 10-6 M SN attenuated Ang II-induced autophagy in podocytes. Furthermore, SN decreased the level of ROS generation in Ang II-induced podocytes via inhibition of NOX subunit p47-phox translocation to the membrane. Conclusion: The appropriate concentration of SN attenuated Ang II-induced podocyte autophagy through ROS generation, at least in part, by regulating NOX subunit p47-phox translocation to the membrane. [ABSTRACT FROM AUTHOR]

Activated M1-type macrophages, which produce inflammatory factors that exacerbate rheumatoid arthritis (RA), represent crucial target cells for inhibiting the disease process. In this study, we developed a novel photoresponsive targeted drug delivery system (TPNPs-HA) that can effectively deliver the hypoxia-activated prodrug tirapazamine (TPZ) specifically to activated macrophages. After administration, this metal-organic framework, PCN-224, constructed uing the photosensitizer porphyrin, exhibits the ability to generate excessive toxic reactive oxygen species (ROS) when exposed to near-infrared light. Additionally, the oxygen-consumed hypoxic environment further activates the chemotherapeutic effect of TPZ, thus creating a synergistic combination of photodynamic therapy (PDT) and hypoxia-activated chemotherapy (HaCT) to promote the elimination of activated M1-type macrophages. The results highlight the significantly potential of this photoresponsive nano-delivery system in providing substantial relief for RA. Furthermore, these findings support its effectiveness in inhibiting the disease process of RA, thereby offering new possibilities for the development of precise and accurate strategies for RA. • A novel strategy for the combined treatment of RA with PDT and HaCT was proposed. • A new nanosized PCN-224 was constructed as multifunctional vehicle for drug delivery. • MOF binds HA as a targeting molecule to activated macrophages through its own positive electrical properties. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury. As a calcium-dependent serine/threonine protein kinase involved in podocyte injury, protein kinase C isoform α (PKCα) was reported to regulate the phosphorylation of p66SHC. However, the role of PKCα/p66SHC in DN remains unknown. Klotho, an anti-aging protein with critical roles in protecting kidney, is expressed predominantly in the kidney and secreted in the blood. Nonetheless, the mechanism underlying amelioration of podocyte injury by Klotho in DN remains unclear. Our data showed that Klotho was decreased in STZ-treated mice and was further declined in diabetic KL ± mice. As expected, Klotho deficiency aggravated diabetes-induced proteinuria and podocyte injury, accompanied by the activation of PKCα and p66SHC. In contrast, overexpression of Klotho partially ameliorated PKCα/p66SHC-mediated podocyte injury and proteinuria. In addition, in vitro experiments showed that activation of PKCα and subsequently increased intracellular reactive oxygen species (ROS) was involved in podocytic apoptosis induced by high glucose (HG), which could be partially reversed by Klotho. Hence, we conclude that Klotho might inhibit PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy. Schematic diagram of the proposed mechanism. HG promotes calcium influx by activating calcium channel (e.g. TRCPC6) in podocytes. Excess intracellular calcium activates PKCα which then contributes to the phosphorylation of p66SHC. Phosphorylated p66SHC then enters mitochondria by altering its configuration. Thereafter, the altered configuration of p66SHC oxidizes cytochrome c (Cytc) releasing a large amount of reactive oxygen species (ROS). Continuous generation of ROS eventually leads to cellular injury and apoptosis of podocytes. However, Klotho (sKL) can function by inhibiting calcium influx induced by HG. SKL reduces intracellular calcium to inhibit PKCα/p66SHC. Therefore, Klotho inhibits continuous generation of ROS eventually ameliorating injury and apoptosis of podocytes. Image 1 • Klotho was inhibited in STZ-treated mice and was further declined in diabetic KL ±mice. • Klotho deficiency aggravated diabetic-induced proteinuria and podocyte injury. • Klotho deficiency aggravated the activation of PKCα and p66SHC. • Klotho reversed activation of PKCα/p66SHC and ROS generation induced by HG in vitro. • Overexpression of Klotho ameliorated PKCα/p66SHC-mediated podocyte injury. [ABSTRACT FROM AUTHOR]