In the human body, copper is an important trace element and is a cofactor for several important enzymes involved in energy production, iron metabolism, neuropeptide activation, connective tissue synthesis, and neurotransmitter synthesis. Copper is also necessary for cellular processes, such as the regulation of intracellular signal transduction, catecholamine balance, myelination of neurons, and efficient synaptic transmission in the central nervous system. Copper is naturally present in some foods and is available as a dietary supplement. Only small amounts of copper are typically stored in the body and a large amount of copper is excreted through bile and urine. Given the critical role of copper in a breadth of cellular processes, local concentrations of copper and the cellular distribution of copper transporter proteins in the brain are important to maintain the steady state of the internal environment. The dysfunction of copper metabolism or regulatory pathways results in an imbalance in copper homeostasis in the brain, which can lead to a myriad of acute and chronic pathological effects on neurological function. It suggests a unique mechanism linking copper homeostasis and neuronal activation within the central nervous system. This article explores the relationship between impaired copper homeostasis and neuropathophysiological progress in brain diseases.

Hydrogen sulfide (H₂S) as an important biological gasotransmitter plays a pivotal role in many physiological and pathological processes. The sensitive and quantitative detection of H₂S level is therefore crucial for precise diagnosis and prognosis evaluation of various diseases but remains a huge challenge due to the lack of accurate and reliable analytical methods in vivo. In this work, we report a smart, H₂S-responsive and depleting nanoplatform (ZNNPs) for quantitative and real-time imaging of endogenous H₂S for early diagnosis and treatment of H₂S-associated diseases. We show that ZNNPs exhibit unexpected NIR conversion (F₁₀₇₀→ F₇₂₀) and ratiometric photoacoustic (PA₆₈₀/PA₉₀₀) signal responsiveness towards H₂S, allowing for sensitive and quantitative visualization of H₂S in acute hepatotoxicity, cerebral hemorrhage model as well as colorectal tumors in living mice. ZNNPs@FA simultaneously scavenges the mitochondrial H₂S in tumors leading to significant ATP reduction and severe mitochondrial damage, together with the activated photodynamic effect, resulting in efficient suppression of colorectal tumor growth in mice. We believe that this platform may provide a powerful tool for studying the vital impacts of H₂S in related diseases.

Hydrogen sulfide (H₂S), a novel gaseous mediator, has been recognized as an important neuromodulator and neuroprotective agent in the central nervous system. The present study was undertaken to study the effects of exogenous H₂S on traumatic brain injury (TBI) and the underlying mechanisms. The effects of exogenous H₂S on TBI were examined by using measurement of brain edema, behavior assessment, propidium iodide (PI) staining, and Western blotting, respectively. Compared to TBI groups, H₂S pretreatment had reduced brain edema, improved motor performance and ameliorated performance in Morris water maze test after TBI. Immunoblotting results showed that H₂S pretreatment reversed TBI-induced cleavage of caspase-3 and decline of Bcl-2, suppressed LC3-II, Beclin-1 and Vps34 activation and maintained p62 level in injured cortex and hippocampus post TBI. The results suggest a protective effect and therapeutic potential of H₂S in the treatment of brain injury and the protective effect against TBI may be associated with regulating apoptosis and autophagy.

Traumatic brain injury (TBI) remains the major cause of disability and mortality worldwide due to the persistent neuroinflammation and neuronal death induced by TBI. Among them, pyroptosis, a specific type of programmed cell death (PCD) triggered by inflammatory signals, plays a significant part in the pathological process after TBI. Inhibition of neuroinflammation and pyroptosis is considered a possible strategy for the treatment of TBI. In our previous study, exogenous hydrogen sulfide(H₂S) exerted a neuroprotective effect after TBI. Here, we developed a surface-fill H₂S-releasing silk fibroin (SF) hydrogel (H₂S@SF hydrogel) to achieve small-dose local administration and avoid volatile and toxic side effects. We used a controlled cortical impact (CCI) to establish a mild TBI model in mice to examine the effect of H₂S@SF hydrogel on TBI-induced pyroptosis. We found that H₂S@SF hydrogel inhibited the expression of H₂S synthase in neurons after TBI and significantly inhibited TBI-induced neuronal pyroptosis. In addition, immunofluorescence staining results showed that the necroptosis protein receptor-interacting serine/threonine-protein kinase 1 (RIPK1) partially colocalized with the pyroptosis protein Gasdermin D (GSDMD) in the same cells. H₂S@SF hydrogel can also inhibit the expression of the necroptosis protein. Moreover, H₂S@SF hydrogel also alleviates brain edema and the degree of neurodegeneration in the acute phase of TBI. The neuroprotective effect of H₂S@SF hydrogel was further confirmed by wire-grip test, open field test, Morris water maze, beam balance test, radial arm maze, tail suspension, and forced swimming test. Lastly, we also measured spared tissue volume, reactive astrocytes and activated microglia to demonstrate H₂S@SF hydrogel impacts on long-term prognosis in TBI. Our study provides a new theoretical basis for the treatment of H₂S after TBI and the clinical application of H₂S@SF hydrogel. STATEMENT OF SIGNIFICANCE: Silk fibroin (SF) hydrogel controls the release of hydrogen sulfide (H₂S) to inhibit neuronal pyroptosis and neuroinflammation in injured brain tissue. In this study, we synthesized a surface-fill H₂S-releasing silk fibroin hydrogel, which could slowly release H₂S to reshape the homeostasis of endogenous H₂S in injured neurons and inhibit neuronal pyroptosis in a mouse model of traumatic brain injury. Meanwhile, H₂S@SF hydrogel could alleviate brain edema and the degree of neurodegeneration, improve motor dysfunction, anxious behavior and memory impairment caused by TBI, reduce tissue loss and ameliorate neuroinflammation. Our study provides a new theoretical basis for the treatment of H₂S after TBI and the clinical application of H₂S@SF hydrogel.

Programmed cell death is pivotal for several physiological processes, including immune defense. Further, it has been implicated in the pathogenesis of developmental disorders and the onset of numerous diseases. Multiple modes of programmed cell death, including apoptosis, pyroptosis, necroptosis, and ferroptosis, have been identified, each with their own unique characteristics and biological implications. In February 2023, Liu Xiaoguang and his team discovered “disulfidptosis,” a novel pathway of programmed cell death. Their findings demonstrated that disulfidptosis is triggered in glucose-starved cells exhibiting high expression of a protein called SLC7A11. Furthermore, disulfidptosis is marked by a drastic imbalance in the NADPH/NADP+ ratio and the abnormal accumulation of disulfides like cystine. These changes ultimately lead to the destabilization of the F-actin network, causing cell death. Given that high SLC7A11 expression is a key feature of certain cancers, these findings indicate that disulfidptosis could serve as the basis of innovative anti-cancer therapies. Hence, this review delves into the discovery of disulfidptosis, its underlying molecular mechanisms and metabolic regulation, and its prospective applications in disease treatment.