The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models.

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × âˆ¼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Temperature-dependent carrier state mediated by H-NS promotes the long-term coexistence of Y. pestis and a phage in soil.

The study of carrier state phages challenged the canonical lytic-lysogenic binary, and carrier state appears to be ubiquitous and ecologically important. However, the mechanisms of the carrier state are not well elucidated due to the limited phage models. Herein, we reported phage HQ103, similar to Escherichia coli phage P2. In contrast to the temperate P2 phage, the HQ103 phage does not insert its genome into the bacterial chromosome and displays a dual behavior depending on the temperature. At 37°C, HQ103 lyses the host and forms clear plaques due to the truncation of repressor CI and mutation of promoter Pc. In contrast, HQ103 maintains a carrier state lifestyle with Y. pestis at an environmental temperature (21°C). Mechanistically, we found that the host-encoded histone-like nucleoid-structuring protein H-NS, which is highly expressed at 21°C to silence the Cox promoter Pe and inhibits the phage lytic cycle. Subsequently, the HQ103 carrier state Y. pestis could grow and co-exist with the phage in the soil at 21°C for one month. Thus, this study reveals a novel carrier state lifestyle of phage HQ103 due to the H-NS mediated xenogeneic silencing and demonstrates that the carrier state lifestyle could promote long-term phage-host coexist in nature.

Oroxin A alleviates early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation.

BACKGROUND: Subarachnoid hemorrhage (SAH), a severe subtype of stroke, is characterized by notably high mortality and morbidity, largely due to the lack of effective therapeutic options. Although the neuroprotective potential of PPARg and Nrf2 has been recognized, investigative efforts into oroxin A (OA), remain limited in preclinical studies. METHODS: SAH was modeled in vivo through filament perforation in male C57BL/6 mice and in vitro by exposing HT22 cells to hemin to induce neuronal damage. Following the administration of OA, a series of methods were employed to assess neurological behaviors, brain water content, neuronal damage, cell ferroptosis, and the extent of neuroinflammation. RESULTS: The findings indicated that OA treatment markedly improved survival rates, enhanced neurological functions, mitigated neuronal death and brain edema, and attenuated the inflammatory response. These effects of OA were linked to the suppression of microglial activation. Moreover, OA administration was found to diminish ferroptosis in neuronal cells, a critical factor in early brain injury (EBI) following SAH. Further mechanistic investigations uncovered that OA facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus, thereby activating the Nrf2/GPX4 pathway. Importantly, OA also upregulated the expression of FSP1, suggesting a significant and parallel protective effect against ferroptosis in EBI following SAH in synergy with GPX4. CONCLUSION: In summary, this research indicated that the PPARg activator OA augmented the neurological results in rodent models and diminished neuronal death. This neuroprotection was achieved primarily by suppressing neuronal ferroptosis. The underlying mechanism was associated with the alleviation of cellular death through the Nrf2/GPX4 and FSP1/CoQ10 pathways.

Pyroptosis-related gene signature elicits immune response in rosacea.

Rosacea is a complex chronic inflammatory skin disorder with high morbidity. Pyroptosis is known as a regulated inflammatory cell death. While its association with immune response to various inflammatory disorders is well established, little is known about its functional relevance of rosacea. So, we aimed to explore and enrich the pathogenesis involved in pyroptosis-related rosacea aggravations. In this study, we evaluated the pyroptosis-related patterns of rosacea by consensus clustering analysis of 45 ferroptosis-related genes (FRGs), with multiple immune cell infiltration analysis to identify the pyroptosis-mediated immune response in rosacea using GSE65914 dataset. The co-co-work between PRGs and WGCNA-revealed hub genes has established using PPI network. FRG signature was highlighted in rosacea using multi-transcriptomic and experiment analysis. Based on this, three distinct pyroptosis-related rosacea patterns (non/moderate/high) were identified, and the notably enriched pathways have revealed through GO, KEGG and GSEA analysis, especially immune-related pathways. Also, the XCell/MCPcount/ssGSEA/Cibersort underlined the immune-related signalling (NK cells, Monocyte, Neutrophil, Th2 cells, Macrophage), whose hub genes were identified through WGCNA (NOD2, MYD88, STAT1, HSPA4, CXCL8). Finally, we established a pyroptosis-immune co-work during the rosacea aggravations. FRGs may affect the progression of rosacea by regulating the immune cell infiltrations. In all, pyroptosis with its mediated immune cell infiltration is a critical factor during the development of rosacea.

Synthesis of Ni decorated MoOx nanorod catalysts for efficient overall urea-water splitting.

Substituting slow oxygen evolution reaction (OER) with thermodynamically favorable urea oxidation reaction (UOR) is considered as one of the feasible strategies for achieving energy-saving hydrogen production. Herein, a uniform layer of NiMoO4 nanorods was grown on nickel foam by a hydrothermal method. Then, a series of Ni-MoOx/NF-X nanorod catalysts comprising Ni/NiO and MoOx (MoO2/MoO3) were prepared through regulating annealing atmosphere and reduction temperature. The optimized Ni-MoOx/NF-3 with a large accessible specific area can act as a bifunctional catalyst for electrocatalytic anodic UOR and cathodic hydrogen evolution reaction (HER). At a current density of 100 mA cm-2, the introduction of urea can significantly reduce the overpotential of Ni-MoOx/NF-3 by 210 mV compared to OER. In addition, Ni-MoOx/NF-3 has a higher intrinsic activity than other catalysts. It only requires -0.21 and 1.38 V to reach 100 mA cm-2 in HER and UOR, respectively. Such an excellent performance can be attributed to the synergistic function between Ni and MoOx. The presence of metallic Ni and reduced MoOx in pairs is beneficial for improving the electrical conductivity and modulating the electronic structure, resulting in enhancing the electrocatalytic performance. When assembling Ni-MoOx/NF-3 into an overall urea-water splitting system, it can achieve energy-saving hydrogen production and effective removal of urea-rich wastewater.

A TonB dependent transporter YncD of Salmonella enterica Serovar Typhi possesses vaccine potential.

Multiple TonB dependent transporters (TBDTs) contribute to bacterial virulence due to the importance roles that their substrates play in bacterial growth, and possess vaccine potential. A putative TBDT, YncD, had been identified as one of in vivo induced antigens during human infection of typhoid fever, and is required for the pathogenicity of Salmonella enterica Serovar Typhi. The present study was aimed to determine the function and immunogenicity of YncD. Homologous recombination method was used to construct an yncD-deletion mutant and cirA-iroN-fepA-deletion mutant from the wild-type S. Typhi Ty2. The growth of mutants and the wild-type strain were assessed in iron-deficient medium, as well as in human macrophage cells. Recombinant YncD protein was expressed and purified using Ni-NTA affinity chromatography and anion exchange. A mouse model was then used to evaluate the immunogenicity and protection efficacy of the recombinant YncD. Antibody levels, serum bactericidal efficiency, passive immune protection, opsonophagocysis were assayed to analyse the immunoprotection mechanism of the recombinant YncD. Our results showed that YncD is associated with the iron-uptake of S. Typhi. The yncD-deletion mutant displayed impaired growth in iron-deficient medium, comparable to that the cirA-iroN-fepA-deletion mutant did. The mutation of yncD markedly decreased bacterial growth within human macrophage cells. Moreover, subcutaneous immunization of mice with recombinant YncD elicited high levels of specific anti-YncD IgG, IgG1 and IgG2a, which protected the immunized mice against the intraperitoneal challenge of S. Typhi, and decreased bacterial burdens in the livers and spleens of the infected mice. Passive immunization using the immunized sera also efficiently protected the mice from the challenge of S. Typhi. Moreover, the immunized sera enhanced in vitro bactericidal activity of complement, and opsonophagocytosis. Our results showed that YncD displays a role in the iron-uptake of S. Typhi and possesses immunogenicity.

Regulated Cell Death of Retinal Ganglion Cells in Glaucoma: Molecular Insights and Therapeutic Potentials.

Glaucoma is a group of diseases characterized by the degeneration of retinal ganglion cells (RGCs) and progressive, irreversible vision loss. High intraocular pressure (IOP) heightens the likelihood of glaucoma and correlates with RGC loss. While the current glaucoma therapy prioritizes lower the IOP; however, RGC, and visual loss may persist even when the IOP is well-controlled. As such, discovering and creating IOP-independent neuroprotective strategies for safeguard RGCs is crucial for glaucoma management. Investigating and clarifying the mechanism behind RGC death to counteract its effects is a promising direction for glaucoma control. Empirical studies of glaucoma reveal the role of multiple regulated cell death (RCD) pathways in RGC death. This review delineates the RCD of RGCs following IOP elevation and optic nerve damage and discusses the substantial benefits of mitigating RCD in RGCs in preserving visual function.

Cold stress causes liver damage by inducing ferroptosis through the p38 MAPK/Drp1 pathway.

Acute extreme cold exposure impairs human health and even causes hypothermia which threatens human life. Liver, as a hub in metabolism and thermogenesis, is vital for cold acclimatization. Although accumulating evidence has suggested that cold exposure can cause liver damage, the underlying mechanisms remain poorly understood. This study investigated the role and underlying mechanisms of ferroptosis in cold stress-induced liver damage. To evaluate the role of ferroptosis in cold stress-induced liver damage, rats were pretreated with ferroptosis inhibitor liproxstatin-1 (Lip-1) before exposed to -10 °C for 8 h. Core body temperature was recorded. The levels of ferroptosis-related indicators were examined with the corresponding assay kits or by western blotting. Hepatic pathological changes were analyzed by hematoxylin-eosin staining and ultrastructural observation. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured to assess liver function. Rats were also pretreated with p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 or Dynamin-related protein 1 (Drp1) inhibitor Mdivi-1 to determine the underlying mechanisms. We found that Lip-1 inhibited ferroptosis, attenuated hepatic pathological damages and blocked the increased ALT and AST levels in cold-exposed rats. Moreover, Mdivi-1 inhibited mitochondrial fission and suppressed ferroptosis. Furthermore, SB203580 and Mdivi-1 administration alleviated cold stress-induced liver injury. Our results suggested that cold stress caused liver damage partially by inducing ferroptosis through the p38 MAPK/Drp1 pathway. These findings might provide an effective preventive and therapeutic target for cold stress-induced liver injury.

Associations between vision impairment and multimorbidity among older Chinese adults: results from the China health and retirement longitudinal study.

BACKGROUND: Although several studies have reported the relationship between vision impairment (VI) and multimorbidity in high-income countries, this relationship has not been reported in low- and middle-income countries. This study aimed to explore the relationship between VI with multimorbidity and chronic conditions among the elderly Chinese population. METHODS: The cross-sectional analysis was applied to data from the China Health and Retirement Longitudinal Study (CHARLS) in 2018. A total of 8,108 participants ≥ 60 years old were included, and 15 chronic conditions were used in this study. Logistic regression analysis was used to analyze the relationship between VI with multimorbidity and chronic conditions. RESULTS: The prevalence of 15 chronic conditions and multimorbidity was higher among the elderly with VI than those without VI. After adjusting for demographic and socioeconomic confounders, 10 chronic conditions were associated with VI (all P < 0.05). Furthermore, positive association was observed between VI and one (odds ratio [OR]: 1.52; 95% confidence intervals [95%CI]: 1.16-2.00; P = 0.002), two (OR: 2.09; 95%CI: 1.61-2.71; P < 0.001), three (OR: 2.87; 95%CI: 2.22-3.72; P < 0.001), four (OR: 3.60; 95%CI: 2.77-4.69; P < 0.001), and five or more (OR: 5.53; 95%CI: 4.32-7.09; P < 0.001) chronic conditions, and the association increased as the number of chronic conditions (P for trend < 0.001). Sensitivity analysis stratified by gender, education, smoking status, and annual per capita household expenditure still found VI to be positively associated with multimorbidity. CONCLUSIONS: For patients older than 60 years, VI was independently associated with multimorbidity and various chronic conditions. This result has important implications for healthcare resource plans and clinical practice, for example, increased diabetes and kidney function screening for patients with VI.

The action logic of the older adults about health-seeking in South Rural China.

BACKGROUND: The Chinese government has invested significant resources to build many rural healthcare stations. However, in the face of convenient medical paths and accessible medical resources, the utilization rate of health services for older adults in rural areas is surprisingly low. This study explored why health-seeking behavior among older adults in rural China was not active. METHODS: Data were collected through participatory rural appraisal (PRA) with 108 participants in 12 villages in southern China. Daily schedule and social and resource mapping were employed to outline the range of activities and the routine of the older adults, as well as in-depth interviews to understand the logic of their healthcare choices. Data collected were analyzed by content analysis. RESULTS: Three themes were generated: (1) perceptions of health status (being healthy or sick): the rural older adults used the ability to handle routine chores as a measure of health status; (2) prioritization of solving symptoms over curing diseases: the older adults preferred the informal self-medication to cope with diseases, as long as there were no symptoms and no pain; (3) 'unpredictable' troubles: they tended to favor the 'optimal' solution of keeping their lives in order rather than the best medical treatment options. CONCLUSION: This study showed that the medical practices of the rural elderly were profoundly influenced by their perceptions of health and their life experiences. In the face of diseases, they tended to keep their lives in order, preferring self-treatment practices that address symptoms or selectively following medical advice rather than medical and science-based clinical solutions. In the future, the construction of rural health care should focus on changing the 'inaccessibility' of healthcare resources at the subjective level of the rural elderly and develop culturally adaptable health education.

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model.

Background: Sepsis, which could cause a systemic inflammatory response, is a life-threatening disease with a high morbidity and mortality rate. There is evidence that brain injury may be related to severe systemic infection induced by sepsis. The brain injury caused by sepsis could increase the risk of mortality in septic patients, which seriously affects the septic patient's prognosis of survival. Although there remains a focus on sepsis research, clinical measures to prevent and treat brain injury in sepsis are not yet available, and the high mortality rate is still a big health burden. Therefore, it is necessary to investigate the new molecules or regulated pathways that can effectively inhibit the progress of sepsis. Objective: NLR family pyrin domain-containing 3 (NLRP3) increased in the procession of sepsis and functioned as the key regulator of pyroptosis. Heat shock factor 1 (HSF1) can protect organs from multiorgan dysfunction syndrome induced by lipopolysaccharides in mice, and NLRP3 could be inhibited by HSF1 in many organs. However, whether HSF1 regulated NLRP3 in sepsis-induced brain injury, as well as the detailed mechanism of HSF1 in brain injury, remains unknown in the sepsis model. In this research, we try to explore the relationship between HSF1 and NLRP3 in a sepsis model and try to reveal the mechanism of HSF1 inhibiting the process of brain injury. Methods: In this study, we used wild-type mice and hsf1 -/- mice for in vivo research and PC12 cells for in vitro research. Real-time PCR and Western blot were used to analyze the expression of HSF1, NLRP3, cytokines, and pyrolytic proteins. EthD-III staining was chosen to detect the pyroptosis of the hippocampus and PC12 cells. Results: The results showed that HSF1 is negatively related to pyroptosis. The pyroptosis in cells of brain tissue was significantly increased in the hsf1 -/- mouse model compared to hsf1 +/+ mice. In PC12 cells, hsf1 siRNA can upregulate pyroptosis while HSF1-transfected plasmid could inhibit the pyroptosis. HSF1 could negatively regulate the NLRP3 pathway in PC12 cells, while hsf1 siRNA enhanced the pyroptosis in PC12 cells, which could be reversed by nlrp3 siRNA. Conclusion: These results imply that HSF1 could alleviate sepsis-induced brain injury by inhibiting pyroptosis through the NLRP3-dependent pathway in brain tissue and PC12 cells, suggesting HSF1 as a potential molecular target for treating brain injury in sepsis clinical studies.

A roadmap to pulmonary delivery strategies for the treatment of infectious lung diseases.

Pulmonary drug delivery is a highly attractive topic for the treatment of infectious lung diseases. Drug delivery via the pulmonary route offers unique advantages of no first-pass effect and high bioavailability, which provides an important means to deliver therapeutics directly to lung lesions. Starting from the structural characteristics of the lungs and the biological barriers for achieving efficient delivery, we aim to review literatures in the past decade regarding the pulmonary delivery strategies used to treat infectious lung diseases. Hopefully, this review article offers new insights into the future development of therapeutic strategies against pulmonary infectious diseases from a delivery point of view.

INFLUENCE OF HIGH MYOPIA ON CHORIOCAPILLARIS PERFUSION AND CHOROIDAL THICKNESS IN DIABETIC PATIENTS WITHOUT DIABETIC RETINOPATHY.

PURPOSE: To investigate the impact of high myopia on choriocapillaris perfusion and choroidal thickness (CT) in diabetic patients without diabetic retinopathy. METHODS: Healthy subjects and patients with diabetes mellitus were recruited from communities in Guangzhou. They were divided into four groups according to the presence of diabetes and high myopia: healthy control (n = 77), diabetes (n = 77), high myopia (n = 77), and diabetes with high myopia (n = 77). Swept-source optical coherence tomography angiography (SS-OCTA) measured choriocapillaris perfusion and CT. Choriocapillaris perfusion was quantified using the choriocapillaris perfusion index (CPI). RESULTS: A total of 308 subjects (308 eyes) were included in the study. The average CPI was 91.11 ± 0.84, 90.16 ± 1.46, 89.80 ± 1.42, and 89.36 ± 1.19% in the control, diabetes, high myopia, and diabetes with high myopia groups, respectively (P < 0.001); the average CT was 227.55 ± 43.13, 205.70 ± 59.66, 158.38 ± 45.24, and 144.22 ± 45.12 µm, respectively (P < 0.001). After adjusting for age and sex, the average CPI decreased 0.95 ± 0.20% (P < 0.001) in the diabetes group, 1.33 ± 0.20% (P < 0.001) in the high myopia group, and 1.76 ± 0.20% (P < 0.001) in the diabetes with high myopia group relative to the control group; the average CT decreased 23.53 ± 8.12 (P = 0.004), 70.73 ± 9.41 (P < 0.001), and 85.90 ± 8.12 µm (P < 0.001), respectively. Further adjustment for other risk factors yielded a similar result. CONCLUSION: Diabetes and high myopia significantly affect CPI and CT, and the presence of both conditions is more damaging to CPI and CT than diabetes or high myopia alone.

Risk analysis of grade ≥ 2 radiation pneumonitis based on radiotherapy timeline in stage III/IV non-small cell lung cancer treated with volumetric modulated arc therapy: a retrospective study.

BACKGROUND: Radiotherapy is an important treatment for patients with stage III/IV non-small cell lung cancer (NSCLC), and due to its high incidence of radiation pneumonitis, it is essential to identify high-risk people as early as possible. The present work investigates the value of the application of different phase data throughout the radiotherapy process in analyzing risk of grade ≥ 2 radiation pneumonitis in stage III/IV NSCLC. Furthermore, the phase data fusion was gradually performed with the radiotherapy timeline to develop a risk assessment model. METHODS: This study retrospectively collected data from 91 stage III/IV NSCLC cases treated with Volumetric modulated arc therapy (VMAT). Patient data were collected according to the radiotherapy timeline for four phases: clinical characteristics, radiomics features, radiation dosimetry parameters, and hematological indexes during treatment. Risk assessment models for single-phase and stepwise fusion phases were established according to logistic regression. In addition, a nomogram of the final fusion phase model and risk classification system was generated. Receiver operating characteristic (ROC), decision curve, and calibration curve analysis were conducted to internally validate the nomogram to analyze its discrimination. RESULTS: Smoking status, PTV and lung radiomics feature, lung and esophageal dosimetry parameters, and platelets at the third week of radiotherapy were independent risk factors for the four single-phase models. The ROC result analysis of the risk assessment models created by stepwise phase fusion were: (area under curve [AUC]: 0.67,95% confidence interval [CI]: 0.52-0.81), (AUC: 0.82,95%CI: 0.70-0.94), (AUC: 0.90,95%CI: 0.80-1.00), and (AUC:0.90,95%CI: 0.80-1.00), respectively. The nomogram based on the final fusion phase model was validated using calibration curve analysis and decision curve analysis, demonstrating good consistency and clinical utility. The nomogram-based risk classification system could correctly classify cases into three diverse risk groups: low-(ratio:3.6%; 0 < score < 135), intermediate-(ratio:30.7%, 135 < score < 160) and high-risk group (ratio:80.0%, score > 160). CONCLUSIONS: In our study, the risk assessment model makes it easy for physicians to assess the risk of grade ≥ 2 radiation pneumonitis at various phases in the radiotherapy process, and the risk classification system and nomogram identify the patient's risk level after completion of radiation therapy.

ZBP1-Mediated Necroptosis: Mechanisms and Therapeutic Implications.

Cell death is a fundamental pathophysiological process in human disease. The discovery of necroptosis, a form of regulated necrosis that is induced by the activation of death receptors and formation of necrosome, represents a major breakthrough in the field of cell death in the past decade. Z-DNA-binding protein (ZBP1) is an interferon (IFN)-inducing protein, initially reported as a double-stranded DNA (dsDNA) sensor, which induces an innate inflammatory response. Recently, ZBP1 was identified as an important sensor of necroptosis during virus infection. It connects viral nucleic acid and receptor-interacting protein kinase 3 (RIPK3) via two domains and induces the formation of a necrosome. Recent studies have also reported that ZBP1 induces necroptosis in non-viral infections and mediates necrotic signal transduction by a unique mechanism. This review highlights the discovery of ZBP1 and its novel findings in necroptosis and provides an insight into its critical role in the crosstalk between different types of cell death, which may represent a new therapeutic option.

Normal vitreous promotes angiogenesi via the epidermal growth factor receptor.

Vitreous, a transparent tissue in our body, contains anti-angiogenesis factors. Our previous work reported that vitreous activates the signaling pathway of epidermal growth factor receptor (EGFR), which plays a critical role in angiogenesis. The aim of this study was to determine the role of EGFR in vitreous-induced angiogenesis-related cellular responses in vitro. Using a pharmacologic and molecular approach, we found that vitreous increased proliferation and migration via EGFR in human umbilical vein endothelial cells (HUVECs). Furthermore, we demonstrated that vitreous promoted tube formation via EGFR in HUVECs. Subsequently, depletion of EGFR using CRISPR/Cas9 and blockage with EGFR inhibitor AG1478 suppressed vitreous-induced Akt activation and cell proliferation, migration, and tube formation in HUVECs. The significance of the angiogenic effect derived from vitreous demonstrates the importance of vitreous in the ocular physiology and the pathobiology of angiogenesis-related ophthalmic diseases, such as proliferative diabetic retinopathy.

How does temperature play a role in the storage of extracellular vesicles?

Extracellular vesicles (EVs) contain specific proteins, lipids, and nucleic acids that can be passed to other cells as signal molecules to alter their function. However, there are many problems and challenges in the conversion and clinical application of EVs. Storage and protection of EVs is one of the issues that need further research. To adapt to potential clinical applications, this type of problem must be solved. This review summarizes the storage practices of EVs in recent years, and explains the impact of temperature on the quality and stability of EVs during storage based on current research, and explains the potential mechanisms involved in this effect as much as possible.

RSK3 mediates necroptosis by regulating phosphorylation of RIP3 in rat retinal ganglion cells.

Receptor-interacting protein 3 (RIP3) plays an important role in the necroptosis signaling pathway. Our previous studies have shown that the RIP3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis occurs in retinal ganglion cell line 5 (RGC-5) following oxygen-glucose deprivation (OGD). However, upstream regulatory pathways of RIP3 are yet to be uncovered. The purpose of the present study was to investigate the role of p90 ribosomal protein S6 kinase 3 (RSK3) in the phosphorylation of RIP3 in RGC-5 cell necroptosis following OGD. Our results showed that expression of RSK3, RIP3, and MLKL was upregulated in necroptosis of RGC-5 after OGD. A computer simulation based on our preliminary results indicated that RSK3 might interact with RIP3, which was subsequently confirmed by co-immunoprecipitation. Further, we found that the application of a specific RSK inhibitor, LJH685, or rsk3 small interfering RNA (siRNA), downregulated the phosphorylation of RIP3. However, the overexpression of rip3 did not affect the expression of RSK3, thereby indicating that RSK3 could be a possible upstream regulator of RIP3 phosphorylation in OGD-induced necroptosis of RGC-5 cells. Moreover, our in vivo results showed that pretreatment with LJH685 before acute high intraocular pressure episodes could reduce the necroptosis of retinal neurons and improve recovery of impaired visual function. Taken together, our findings suggested that RSK3 might work as an upstream regulator of RIP3 phosphorylation during RGC-5 necroptosis.

Current status and potential role of circular RNAs in neurological disorders.

Given the importance of non-coding RNAs in modulating normal brain functions and their implications in the treatment of neurological disorders, non-coding RNA-based diagnostic and therapeutic strategies have shown great clinical potential. Circular RNAs (circRNAs) have emerged as potentially important players in this field. Recent studies have indicated that circRNAs might play vital roles in Alzheimer's disease, Parkinson's disease, ischemic brain injury, and neurotoxicity. However, the mechanisms of action of circRNAs have not been fully characterized. We aimed to review recent advances in circRNA research in the brain to provide new insights on the roles of circRNAs in neurological disorders.

Inhibition of HSP90α protects cultured neurons from oxygen-glucose deprivation induced necroptosis by decreasing RIP3 expression.

Heat shock protein 90α (HSP90α) maintains cell stabilization and regulates cell death, respectively. Recent studies have shown that HSP90α is involved in receptor interacting protein 3 (RIP3)-mediated necroptosis in HT29 cells. It is known that oxygen and glucose deprivation (OGD) can induce necroptosis, which is regulated by RIP3 in neurons. However, it is still unclear whether HSP90α participates in the process of OGD-induced necroptosis in cultured neurons via the regulation of RIP3. Our study found that necroptosis occurs in primary cultured cortical neurons and PC-12 cells following exposure to OGD insult. Additionally, the expression of RIP3/p-RIP3, MLKL/p-MLKL, and the RIP1/RIP3 complex (necrosome) significantly increased following OGD, as measured through immunofluorescence (IF) staining, Western blotting (WB), and immunoprecipitation (IP) assay. Additionally, data from computer simulations and IP assays showed that HSP90α interacts with RIP3. In addition, HSP90α was overexpressed following OGD in cultured neurons, as measured through WB and IF staining. Inhibition of HSP90α in cultured neurons, using the specific inhibitor, geldanamycin (GA), and siRNA/shRNA of HSP90α, protected cultured neurons from necrosis. Our study showed that the inhibitor of HSP90α, GA, rescued cultured neurons not only by decreasing the expression of total RIP3/MLKL, but also by decreasing the expression of p-RIP3/p-MLKL and the RIP1/RIP3 necrosome. In this study, we reveal that inhibition of HSP90α protects primary cultured cortical neurons and PC-12 cells from OGD-induced necroptosis through the modulation of RIP3 expression.