Mechanochemical Backbone Editing for Controlled Degradation of Vinyl Polymers.

The chemically inert nature of fully saturated hydrocarbon backbones endows vinyl polymers with desirable durability, but it also leads to their significant environmental persistence. Enhancing the sustainability of these materials requires a pivotal yet challenging shift: transforming the inert backbone into one that is degradable. Here, we present a versatile platform for mechanochemically editing the fully saturated backbone of vinyl polymers towards degradable polymer chains by integrating cyclobutene-fused succinimide (CBS) units along backbone through photo-iniferter reversible addition-fragmentation chain-transfer (RAFT) copolymerization. Significantly, the evenly insertion of CBS units does not compromise thermal or chemical stability but rather offers a means to adjust the properties of polymethylacrylate (PMA). Meanwhile, reactive acyclic imide units can be selectively introduced to the backbone through mechanochemical activation (pulse ultrasonication or ball-milling grinding) when required. Subsequent hydrolysis of the acyclic imide groups enables efficient degradation, yielding telechelic oligomers. This approach holds promise for inspiring the design and modification of more environmentally friendly vinyl polymers through backbone editing.

Brain structure and functional connectivity linking childhood cumulative trauma to COVID-19 vicarious traumatization.

BACKGROUND: The COVID-19 pandemic has caused some individuals to experience vicarious traumatization (VT), an adverse psychological reaction to those who are primarily traumatized, which may negatively impact one's mental health and well-being and has been demonstrated to vary with personal trauma history. The neural mechanism of VT and how past trauma history affects current VT remain largely unknown. This study aimed to identify neurobiological markers that track individual differences in VT and reveal the neural link between childhood cumulative trauma (CCT) and VT. METHODS: We used structural and resting-state functional magnetic resonance imaging before the pandemic to identify prospective brain markers for COVID-related VT by correlating individuals' VT levels during the pandemic with the gray matter volume (GMV) and seed-based resting-state functional connectivity (RSFC) and examined how these brain markers linked CCT to VT in a sample of general young adults (N = 115/100). RESULTS: Whole-brain GMV-behavior correlation analysis showed that VT was positively associated with GMV in the right dorsolateral prefrontal gyrus (DLPFC). Using the cluster derived from the GMV-behavior correlation analysis as the seed region, we further revealed that the RSFC between the right DLPFC and right precuneus was negatively associated with VT. Importantly, the right DLPFC volume and DLPFC-precuneus RSFC mediated the effect of CCT on VT. These findings remained unaffected by factors such as family socioeconomic status, other stressful life events, and general mental health. CONCLUSIONS: Overall, our study presents structural and functional brain markers for VT and highlights these brain-based markers as a potential neural mechanism linking CCT to COVID-related VT, which has implications for treating and preventing the development of trauma-related mental disorders.

Epidemiological variations and trends in glaucoma burden in the Belt and Road countries.

BACKGROUND: Analyzing the glaucoma burden in "Belt and Road" (B&R) countries based on age, gender, and risk factors from 1990 to 2019 in order to provide evidence for future prevention strategies. METHODS: We applied global burden of disease(GBD) 2019 to compare glaucoma prevalence and Years lived with disabilities (YLDs) from 1990 to 2019 in the B&R countries. Trends of disease burden between 1990 and 2019 were evaluated using the average annual percent change and the 95% uncertainty interval (UI) were reported. RESULTS: From 1990 to 2019, most B&R countries showed a downward trend in age-standardized prevalence and YLDs (all P < 0.05). Additionally, only the age-standardized YLDs in males of Pakistan has a 0.35% increase (95%CI:0.19,0.50,P < 0.001), and most B&R countries has a decline(all P < 0.05) in age-standardized YLDs in every 5 years age group after 45 years old except for Pakistan(45-79 years and > 85 years), Malaysia(75-84 years), Brunei Darussalam(45-49 years), Afghanistan(70-79 years). Finally, in all Central Asian countries, the age-standardized YLDs due to glaucoma caused by fasting hyperglycemia demonstrated have an increase between 1990 and 2019 (all P < 0.05), but Armenia and Mongolia have a decrease between 2010 and 2019 (all P < 0.05). CONCLUSION: The prevalence of glaucoma continues to pose a significant burden across regions, ages, and genders in countries along the "B&R". It is imperative for the "B&R" nations to enhance health cooperation in order to collaboratively tackle the challenges associated with glaucoma.

Genetic dissection of ten photosynthesis-related traits based on InDel- and SNP-GWAS in soybean.

KEY MESSAGE: A total of 416 InDels and 112 SNPs were significantly associated with soybean photosynthesis-related traits. GmIWS1 and GmCDC48 might be related to chlorophyll fluorescence and gas-exchange parameters, respectively. Photosynthesis is one of the main factors determining crop yield. A better understanding of the genetic architecture for photosynthesis is of great significance for soybean yield improvement. Our previous studies identified 5,410,112 single nucleotide polymorphisms (SNPs) from the resequencing data of 219 natural soybean accessions. Here, we identified 634,106 insertions and deletions (InDels) from these 219 accessions and used these InDel variations to perform principal component and linkage disequilibrium analysis of this population. The genome-wide association study (GWAS) were conducted on six chlorophyll fluorescence parameters (chlorophyll content, light energy absorbed per reaction center, quantum yield for electron transport, probability that a trapped exciton moves an electron into the electron transport chain beyond primary quinone acceptor, maximum quantum yield of photosystem II primary photochemistry in the dark-adapted state, performance index on absorption basis) and four gas-exchange parameters (intercellular carbon dioxide concentration, stomatal conductance, net photosynthesis rate, transpiration rate) and revealed 416 significant InDels and 112 significant SNPs. Based on GWAS results, GmIWS1 (encoding a transcription elongation factor) and GmCDC48 (encoding a cell division cycle protein) with the highest expression in the mapping region were determined as the candidate genes responsible for chlorophyll fluorescence and gas-exchange parameters, respectively. Further identification of favorable haplotypes with higher photosynthesis, seed weight and seed yield were carried out for GmIWS1 and GmCDC48. Overall, this study revealed the natural variations and candidate genes underlying the photosynthesis-related traits based on abundant phenotypic and genetic data, providing valuable insights into the genetic mechanisms controlling photosynthesis and yield in soybean.

A Multifunctional Metal-Phenolic Nanocoating on Bone Implants for Enhanced Osseointegration via Early Immunomodulation.

Surface modification is an important approach to improve osseointegration of the endosseous implants, however it is still desirable to develop a facile yet efficient coating strategy. Herein, a metal-phenolic network (MPN) is proposed as a multifunctional nanocoating on titanium (Ti) implants for enhanced osseointegration through early immunomodulation. With tannic acid (TA) and Sr2+ self-assembled on Ti substrates, the MPN coatings provided a bioactive interface, which can facilitate the initial adhesion and recruitment of bone marrow mesenchymal stem cells (BMSCs) and polarize macrophage toward M2 phenotype. Furthermore, the TA-Sr coatings accelerated the osteogenic differentiation of BMSCs. In vivo evaluations further confirmed the enhanced osseointegration of TA-Sr modified implants via generating a favorable osteoimmune microenvironment. In general, these results suggest that TA-Sr MPN nanocoating is a promising strategy for achieving better and faster osseointegration of bone implants, which can be easily utilized in future clinical applications.

Changing profiles of the burden of Alzheimer's disease and other dementias attributable to smoking in the belt and road initiative countries: A secondary analysis of global burden of disease 2019.

Objectives: This study was aimed at analyzing the burden and trend of Alzheimer's disease and other dementias attributed to smoking (SADD) in the Belt and Road Initiative (BRI) countries during 1990-2019. Methods: Data from The 2019 Global Burden of Disease Study was used to extract information on the burden of SADD in terms of the numbers and age-standardized rate of mortality (ASMR) and disability-adjusted life years (ASDALR) in the BRI countries for 1990-2019. The average annual percent change (AAPC) was used to analyze the temporal trends of ASDALR from 1990 to 2019 and in the final decade by Joinpoint regression analysis. Results: The DALYs of SADD were the highest in China, India, and the Russian Federation in 1990 and in Lebanon, Montenegro and Bosnia, and Herzegovina in 2019. From 1990 to 2019, the ASDALR in China had increased from 55.50/105 to 66.18/105, but decreased from 2010 to 2019, while that of India had declined from 32.84/105 to 29.35/105, but increased from 2010 to 2019. The ASDALR showed the fastest increase in the Russian Federation, with AAPC of 1.97% (95% confidence interval [CI]: 1.77%, 2.16%), and the fastest decline in Sri Lanka, with AAPC of -2.69% (95% CI: 2.79%, -2.59%). ASMR and ASDALR from SADD showed a substantial decline during 1990-2019 both globally and in the different socio-demographic index (SDI) regions (all P < 0.05, except for the high-middle-SDI region). Compared to the rates in males, the AAPC in ASDALR of females was significantly greater in 20 countries(all P < 0.05). In the age group of 20-54 years, the DALYs rate showed a decreasing trend only in 13 members in the low-SDI region (all P < 0.05). Conclusion: Under the premise of eliminating the differences, mobilizing resources in the country itself, the BRI organization, and globally will help reduce the global SADD burden and achieve healthy and sustainable development.

Hydrogen sulfide improves endothelial barrier function by modulating the ubiquitination degradation of KLF4 through TRAF7 S-sulfhydration in diabetic aorta.

Anomalous vascular endothelium significantly contributes to various cardiovascular diseases. VE-cadherin plays a vital role in governing the endothelial barrier. Krüppel-like factor 4(KLF4), as a transcription factor, which binds the VE-cadherin promoter and enhances its transcription. Tumor necrosis factor receptor-associated factor 7 (TRAF7) is an E3 ubiquitin ligase that has been shown to modulate the degradation of KLF4. H2S can covalently modify cysteine residues on proteins through S-sulfhydration, thereby influencing the structure and functionality of the target protein. However, the role of S-sulfhydration on endothelial barrier integrity remains to be comprehensively elucidated. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates endothelial integrity and its underlying mechanism. In this study, we observed that protein S-sulfhydration was reduced in the endothelium during diabetes and TRAF7 was the main target. Overexpression of TRAF7-Cys327 mutant could mitigate the endothelial barrier damage by weakening TRAF7 interaction with KLF4 and reducing ubiquitination degradation of KLF4. In conclusion, our research demonstrates that H2S plays a pivotal role in regulating S-sulfhydration of TRAF7 at Cys327. This regulation effectively inhibits the ubiquitin-mediated degradation of KLF4, resulting in an upregulation of VE-cadherin levels. This molecular mechanism contributes to the prevention of endothelial barrier damage.

Functional and Degradable Polyester-co-polyethers from CO2, Butadiene, and Epoxides.

Carbon dioxide (CO2), as a renewable and nontoxic C1 feedstock, has been recognized as an ideal comonomer to prepare sustainable materials. In this regard, substantial focus has been dedicated to the ring-opening copolymerization of CO2 and epoxides, which results in the creation of aliphatic polycarbonates in most cases. Here, we report an unprecedented strategy to synthesize functional and degradable polyester-co-polyethers from CO2, butadiene, and epoxides via a CO2/butadiene-derived δ-valerolactone intermediate (EVP). Utilizing a chromium salen complex as the catalyst, the copolymerization of EVP and epoxides was successfully achieved to produce CO2/butadiene/epoxide terpolymers. The obtained polyester-co-polyethers with varied 39-93 mol % EVP content (equal to 18-28 wt % CO2 incorporation) show high thermal stability, tunable glass-transition temperatures, on-demand functionality, and good chemical degradability. This method extends the potential to access functional CO2-based polymers.

Empathy with nature promotes pro-environmental attitudes in preschool children.

This study aimed to explore whether empathy with nature (i.e., the tendency to understand and share the emotional experience of the natural world) contributes to pro-environmental attitudes in early childhood. In a correlational investigation (Study 1), 138 (Mage = 57.78 months) preschool children completed a battery of tasks to measure their pro-environmental attitudes, empathy with nature, and empathy with humans. We found that empathy with nature positively predicts pro-environmental attitudes, even beyond the predictive power of empathy with humans. In a quasi-experimental investigation (Study 2), 46 children from two parallel classes in the same preschool were recruited as the intervention (n = 23, Mage = 66.74 months) and control (n = 23, Mage = 67.61 months) groups. An intervention session that aimed to induce empathy with nature was applied to the intervention group, whereas an active control teaching session was applied to the control group. After the intervention, the intervention group demonstrated greater pro-environmental attitudes than did the control group. Together, our studies provide converging evidence that empathy with nature promotes pro-environmental attitudes in early childhood, further implying the value of integrating empathy with nature in early childhood environmental education.

Patterns and trends of mortality from metastatic colorectal cancer in Shanghai, China from 2005 to 2021: a population-based retrospective analysis.

PURPOSE: Metastatic colorectal cancer (mCRC) is the leading cause of CRC deaths, however, the relative epidemiological research was insufficient. We aimed to analyze the patterns and trends of mortality of mCRC in Shanghai with a more complete system for monitoring the cause of death of the population and find potential methods to reduce the burden of CRC in China. METHODS: Mortality data from 2005 to 2021 of mCRC deaths were obtained from the mortality registration system in Shanghai. We analyzed the crude mortality rates, age-standardized mortality rates, and rates of years of life lost (YLL rates) of mCRC. In addition, the trends were quantified using Joinpoint Regression software. RESULTS: A total of 4,386 mCRC deaths were included, with 1,937 (44.16%) liver metastases and 1,061 (24.19%) lung metastases. The crude mortality rate and age-standardized mortality rate of mCRC were 9.09 per 105 person-years and 3.78 per 105 person-years, respectively. The YLL was 50,533.13 years, and the YLL rate was 104.67 per 105 person-years. The overall annual crude mortality rate of mCRC increased by 1.47% (95% CI 0.28-2.68%, P < 0.001) from 2005 to 2021. The crude mortality rate of mCRC increased by 3.20% per year (95% CI 1.80-4.70%, P < 0.001) from 2005 to 2013, but the trend of mortality growth remained stable from 2013 to 2021. The YLL rates remained stable between 2005 and 2021. CONCLUSIONS: Population aging was the most likely factor responsible for the increase in CRC mortality in Pudong. Physical examinations and screenings for the elderly were possible reasons for reducing the burden of CRC in fast-growing regions.

Clinical relevance of ORCs in predicting prognosis and immunotherapy outcomes: A pan-cancer analysis.

BACKGROUND: The origin recognition complex (ORC) consists of six subunits and mediates DNA replication by binding to its origin. Recent studies show that ORCs are closely related to various biological processes in tumors. However, a comprehensive study of ORCs in pan-cancer has not been conducted. RESULTS: A systematic evaluation of the expression, mutation, and prognostic significance of ORCs was conducted across cancer types using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The single-sample Gene Set Enrichment Analysis (ssGSEA) was performed using R package "Gene Set Variation Analysis (GSVA)" to evaluate ORC score. ORC score was significantly elevated in most cancers and linked with an inferior prognosis. It was positively related to the G2/M checkpoint and DNA repair pathways. An elevated ORC score also correlated with tumor mutation burden (TMB)/ microsatellite instability (MSI). A prognosis analysis suggested that high ORC scores were associated with heightened immunotherapeutic sensitivity. CONCLUSIONS: Our research elucidates the genomic changes associated with and clinical relevance of ORCs in cancer and provides unique insights for future investigation of ORCs in immunotherapy.

Tandem Catalysis inside Double-Shelled Nanocages with Separated and Tunable Atomic Catalyst Sites for High Performance Lithium-Sulfur Batteries.

Single-atomic catalysts are effective in mitigating the shuttling effect and slow redox kinetics of lithium polysulfides (LiPSs) in lithium-sulfur (Li-S) batteries, but their ideal performance has yet to be achieved due to the multi-step conversion of LiPSs requiring multifunctional active sites for tandem catalysis. Here double-shelled nano-cages (DSNCs) have been developed to address this challenge, featuring separated and tunable single-atom sites as nano reactors that trigger tandem catalysis and promote the efficient electrochemical conversion of LiPSs. This enables high capacity and durable Li-S batteries. The DSNCs, with inner Co-N4 and outer Zn-N4 sites (S/CoNC@ZnNC DSNCs), exhibit a high specific capacity of 1186 mAh g-1 at 1 C, along with a low capacity fading rate of 0.063% per cycle over 500 cycles. Even with a high sulfur loading (4.2 mg cm-2) and a low E/S ratio (6 µL mg-1), the cell displays excellent cycling stability. Moreover, the Li-S pouch cells are capable of stable cycling for more than 160 cycles. These results demonstrate the feasibility of driving successive sulfur conversion reactions with separated active sites, and are expected to inspire further catalyst design for high performance Li-S batteries.

CircMETTL15 induces TMTC3 production by absorbing miR-944 to promote hepatocellular carcinoma cell malignancy.

Previous data have suggested the involvement of circular RNA (circRNA) in hepatocellular carcinoma (HCC) progression. Up to now, the effect of circMETTL15 on HCC development remains unknown. This study aims to analyze the function of circMETTL15 in HCC development and the underlying mechanism. RNA expression of circMETTL15, miR-944, and transmembrane O-mannosyltransferase targeting cadherins 3 (TMTC3) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was evaluated by Western blot analysis assay or immunohistochemistry assay. Cell proliferation was investigated by cell counting kit-8 assay, 5-Ethynyl-29-deoxyuridine (EdU) assay, and cell colony formation assay. Cell migration and invasion were assessed by wound-healing assay and transwell assay, respectively. Angiogenic capacity was analyzed by tube formation assay. Dual-luciferase reporter assay and RNA immunoprecipitation assay were conducted to identify the interplay between miR-944 and circMETTL15 or TMTC3. Xenograft mouse model assay was conducted to reveal the effect of circMETTL15 on tumor formation in vivo. CircMETTL15 and TMTC3 expression were significantly upregulated, while miR-944 expression was downregulated in HCC tissues and cells. CircMETTL15 knockdown led to decreased cell proliferation, migration, invasion, and tube formation. Besides, the inhibitors of miR-944, a target miRNA of circMETTL15, partially restored circMETTL15 silencing-mediated effects on the proliferation, migration, invasion, and tube formation of HCC cells. MiR-944 overexpression also inhibited HCC cell malignancy by targeting TMTC3. Furthermore, circMETTL15 absence inhibited tumor formation by regulating miR-944 and TMTC3 in vivo. In conclusion, circMETTL15 induced HCC development through the miR-944/TMTC3 pathway, raising the potential of circMETTL15 as a target for HCC therapy.

Tuning Intermediates Adsorption and C─N Coupling for Efficient Urea Electrosynthesis Via Doping Ni into Cu.

Simultaneous electrochemical reduction of nitrite and carbon dioxide (CO2 ) under mild reaction conditions offers a new sustainable and low-cost approach for urea synthesis. However, the development of urea electrosynthesis thus far still suffers from low selectivity due to the high energy barrier of * CO formation and the subsequent C─N coupling. In this work, a highly active dendritic Cu99 Ni1 catalyst is developed to enable the highly selective electrosynthesis of urea from co-reduction of nitrite and CO2 , reaching a urea Faradaic efficiency (FE) and production rate of 39.8% and 655.4 µg h-1  cm-2 , respectively, at -0.7 V versus reversible hydrogen electrode (RHE). In situ Fourier-transform infrared spectroscopy (FT-IR) measurements together with density functional theory (DFT) calculations demonstrate that Ni doping into Cu can significantly enhance the adsorption energetics of the key reaction intermediates and facilitate the C─N coupling. This work not only provides a new strategy to design efficient electrocatalysts for urea synthesis but also offers deep insights into the mechanism of C─N coupling during the co-reduction of nitrite and CO2 .

Circulating tumor cells as potential prognostic biomarkers for early-stage pancreatic cancer: A systematic review and meta-analysis.

BACKGROUND: Pancreatic cancer is difficult to be diagnosed early clinically, while often leads to poor prognosis. If optimal personalized treatment plan can be provided to pancreatic cancer patient at an earlier stage, this can greatly improve overall survival (OS). Circulating tumor cells (CTCs) are a collective term for various types of tumor cells present in the peripheral blood (PB), which are formed by detachment during the development of solid tumor lesions. Most CTCs undergo apoptosis or are phagocytosed after entering the PB, whereas a few can escape and anchor at distal sites to develop metastasis, increasing the risk of death for patients with malignant tumors. AIM: To investigate the significance of CTCs in predicting the prognosis of early pancreatic cancer patients. METHODS: The PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine, and ChinaInfo databases were searched for articles published through December 2022. Studies were considered qualified if they included patients with early pancreatic cancer, analyzed the prognostic value of CTCs, and were full papers reported in English or Chinese. Researches were selected and assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and the Newcastle-Ottawa Scale criteria. We used a funnel plot to assess publication bias. RESULTS: From 1595 publications, we identified eight eligible studies that collectively enrolled 355 patients with pancreatic cancer. Among these original studies, two were carried out in China; three in the United States; and one each in Italy, Spain, and Norway. All eight studies analyzed the relevance between CTCs and the prognosis of patients with early-stage pancreatic cancer after surgery. A meta-analysis showed that the patients that were positive pre-treatment or post-treatment for CTCs were associated with decreased OS [hazard ratio (HR) = 1.93, 95% confidence interval (CI): 1.197-3.126, P = 0.007] and decreased relapse-free/disease-free/progression-free survival (HR = 1.27, 95%CI: 1.137-1.419, P < 0.001) in early-stage pancreatic cancer. Additionally, the results suggest no statistically noticeable publication bias for overall, disease-free, progression-free, and recurrence-free survival. CONCLUSION: This pooled meta-analysis shows that CTCs, as biomarkers, can afford reliable prognostic information for patients with early-stage pancreatic cancer and help develop individualized treatment plans.

Psychometric testing of the 10-item perceived stress scale for Chinese nurses.

BACKGROUND: Nurses bear a lot of stressors at work. The 10-item Perceived Stress Scale (PSS-10) is a widely used self-reported scale for measuring the global perception of stress. However, there is a lack of use of the PSS-10 in Chinese nurses. This study aimed to test the psychometric properties of the PSS-10 among Chinese nurses. METHODS: A total of 708 Chinese nurses completed the PSS-10, the Big Five Inventory (BFI), and the Depression Anxiety and Stress Scale (DASS). Confirmatory factor analysis (CFA) tested the factor structure of the PSS-10. Cronbach's α and test-retest correlation examined the scale reliability. Pearson correlation and hierarchical regression analyses tested the convergent, discriminant and criterion validity of the PSS-10. RESULTS: CFA revealed that a two-factor model fits the structure of the PSS-10 in Chinese nurses (χ2/df = 6.25, p < 0.001; comparative fit index [CFI] = 0.94, non-normal fit index [NNFI] = 0.92, Tucker-Lewis index [TLI] = 0.91, root mean square error of approximation [RMSEA] = 0.08, standardized root mean square residual [SRMR] = 0.05). The scale demonstrated adequate internal consistency (α = 0.86) and test-retest reliability (r = 0.66, p < 0.001), satisfactory convergent and discriminant validity with relations to Big Five personalities, as well as good criterion validity such that the PSS-10 score could explain incremental variance in predicting anxiety, depression and stress. CONCLUSIONS: Our findings suggest that PSS-10 is a reliable and valid measure of perceived stress among Chinese nurses and can be used in future research and practice on stress management and coping in Chinese nurses.

Exogenous H2S initiating Nrf2/GPx4/GSH pathway through promoting Syvn1-Keap1 interaction in diabetic hearts.

Excessive ROS accumulation contributes to cardiac injury in type 2 diabetes mellitus. Hydrogen sulfide (H2S) is a vital endogenous gasotransmitter to alleviate cardiac damage in diabetic cardiomyopathy (DCM). However, the underlying mechanisms remain unclear. In this study, we investigated the effects of NaHS administration in db/db mice via intraperitoneal injection for 20 weeks and the treatment of high glucose (HG), palmitate (PA) and NaHS in HL-1 cardiomyocytes for 48 h, respectively. H2S levels were decreased in hearts of db/db mice and HL-1 cardiomyocytes exposed to HG and PA, which were restored by NaHS. Exogenous H2S activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4)/glutathione (GSH) pathway, suppressed ferroptosis and mitigated mitochondrial apoptosis in db/db mice. However, these effects were abrogated after Nrf2 knockdown. NaHS treatment elevated the ubiquitination level of Kelch-like ECH-associated protein (Keap1) by preserving its E3 ligase synoviolin (Syvn1), resulting in Nrf2 nuclear translocation. H2S facilitated the sulfhydration of Syvn1-cys115 site, a post-translational modification. Transfecting Syvn1 C115A in cardiomyocytes exposed to HG and PA partially attenuated the effects of NaHS on Nrf2 and cell death. Our findings suggest that exogenous H2S regulates Nrf2/GPx4/GSH pathway by promoting the Syvn1-Keap1 interaction to reduce ferroptosis and mitochondrial apoptosis in DCM.

Exogenous H2 S promotes ubiquitin-mediated degradation of SREBP1 to alleviate diabetic cardiomyopathy via SYVN1 S-sulfhydration.

BACKGROUND: Diabetic cardiomyopathy, a distinctive complication of diabetes mellitus, has been correlated with the presence of intracellular lipid deposits. However, the intricate molecular mechanisms governing the aberrant accumulation of lipid droplets within cardiomyocytes remain to be comprehensively elucidated. METHODS: Both obese diabetic (db/db) mice and HL-1 cells treated with 200 µmol/L palmitate and 200 µmol/L oleate were used to simulate type 2 diabetes conditions. Transmission electron microscopy is employed to assess the size and quantity of lipid droplets in the mouse hearts. Transcriptomics analysis was utilized to interrogate mRNA levels. Lipidomics and ubiquitinomics were employed to explore the lipid composition alterations and proteins participating in ubiquitin-mediated degradation in mice. Clinical data were collected from patients with diabetes-associated cardiomyopathy and healthy controls. Western blot analysis was conducted to assess the levels of proteins linked to lipid metabolism, and the biotin-switch assay was employed to quantify protein cysteine S-sulfhydration levels. RESULTS: The administration of H2 S donor, NaHS, effectively restored hydrogen sulfide levels in both the cardiac tissue and plasma of db/db mice (+7%, P < 0.001; +5%, P < 0.001). Both db/db mice (+210%, P < 0.001) and diabetic patients (+83%, P = 0.22, n = 5) exhibit elevated plasma triglyceride levels. Treatment with GYY4137 effectively lowers triglyceride levels in db/db mice (-43%, P = 0.007). The expression of cystathionine gamma-lyase and HMG-CoA reductase degradation protein 1 (SYVN1) was decreased in db/db mice compared with the wild-type mice (cystathionine gamma-lyase: -31%, P = 0.0240; SYVN1: -35%, P = 0.01), and NaHS-treated mice (SYVN1: -31%, P = 0.03). Conversely, the expression of sterol regulatory element-binding protein 1 (SREBP1) was elevated (+91%, P = 0.007; +51%, P = 0.03 compared with control and NaHS-treated mice, respectively), along with diacylglycerol O-acyltransferase 1 (DGAT1) (+95%, P = 0.001; +35%, P = 0.02) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) (+88%, P = 0.01; +22%, P = 0.32). Exogenous H2 S led to a reduction in lipid droplet formation (-48%, P < 0.001), restoration of SYVN1 expression, modification of SYVN1's S-sulfhydration status and enhancement of SREBP1 ubiquitination. Overexpression of SYVN1 mutated at Cys115 decreased SREBP1 ubiquitination and increased the number of lipid droplets. CONCLUSIONS: Exogenous H2 S enhances ubiquitin-proteasome degradation of SREBP1 and reduces its nuclear translocation by modulating SYVN1's cysteine S-sulfhydration. This pathway limits lipid droplet buildup in cardiac myocytes, ameliorating diabetic cardiomyopathy.

Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1.

Gastric cancer stem cells (GCSCs) are self-renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA-seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1-CreERT2; Rosa26Tdtomato and Tff1-CreERT2; Apcfl/fl ; p53fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest-specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency-induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency.