FUS Regulates Activity of MicroRNA-Mediated Gene Silencing.

MicroRNA-mediated gene silencing is a fundamental mechanism in the regulation of gene expression. It remains unclear how the efficiency of RNA silencing could be influenced by RNA-binding proteins associated with the microRNA-induced silencing complex (miRISC). Here we report that fused in sarcoma (FUS), an RNA-binding protein linked to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), interacts with the core miRISC component AGO2 and is required for optimal microRNA-mediated gene silencing. FUS promotes gene silencing by binding to microRNA and mRNA targets, as illustrated by its action on miR-200c and its target ZEB1. A truncated mutant form of FUS that leads its carriers to an aggressive form of ALS, R495X, impairs microRNA-mediated gene silencing. The C. elegans homolog fust-1 also shares a conserved role in regulating the microRNA pathway. Collectively, our results suggest a role for FUS in regulating the activity of microRNA-mediated silencing.

Comparative transcriptomic analysis provides insights into the genetic networks regulating oil differential production in oil crops.

BACKGROUND: Plants differ more than threefold in seed oil contents (SOCs). Soybean (Glycine max), cotton (Gossypium hirsutum), rapeseed (Brassica napus), and sesame (Sesamum indicum) are four important oil crops with markedly different SOCs and fatty acid compositions. RESULTS: Compared to grain crops like maize and rice, expanded acyl-lipid metabolism genes and relatively higher expression levels of genes involved in seed oil synthesis (SOS) in the oil crops contributed to the oil accumulation in seeds. Here, we conducted comparative transcriptomics on oil crops with two different SOC materials. In common, DIHYDROLIPOAMIDE DEHYDROGENASE, STEAROYL-ACYL CARRIER PROTEIN DESATURASE, PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE, and oil-body protein genes were both differentially expressed between the high- and low-oil materials of each crop. By comparing functional components of SOS networks, we found that the strong correlations between genes in "glycolysis/gluconeogenesis" and "fatty acid synthesis" were conserved in both grain and oil crops, with PYRUVATE KINASE being the common factor affecting starch and lipid accumulation. Network alignment also found a conserved clique among oil crops affecting seed oil accumulation, which has been validated in Arabidopsis. Differently, secondary and protein metabolism affected oil synthesis to different degrees in different crops, and high SOC was due to less competition of the same precursors. The comparison of Arabidopsis mutants and wild type showed that CINNAMYL ALCOHOL DEHYDROGENASE 9, the conserved regulator we identified, was a factor resulting in different relative contents of lignins to oil in seeds. The interconnection of lipids and proteins was common but in different ways among crops, which partly led to differential oil production. CONCLUSIONS: This study goes beyond the observations made in studies of individual species to provide new insights into which genes and networks may be fundamental to seed oil accumulation from a multispecies perspective.

A novel compound alleviates oxidative stress via PKA/CREB1-mediated DJ-1 upregulation.

Oxidative stress is one of the major culprits causing dopaminergic neuron loss in Parkinson's disease (PD). DJ-1 is a protein with multiple actions against oxidative stress, apoptosis, neuroinflammation, etc. DJ-1 expression is decreased in sporadic PD, therefore increasing DJ-1 expression might be beneficial in PD treatment. However, drugs known to upregulate DJ-1 are still lacking. In this study, we identified a novel DJ-1-elevating compound called ChemJ through luciferase assay-based high-throughput compound screening in SH-SY5Y cells and confirmed that ChemJ upregulated DJ-1 in SH-SY5Y cell line and primary cortical neurons. DJ-1 upregulation by ChemJ alleviated MPP+-induced oxidative stress. In exploring the underlying mechanisms, we found that the transcription factor CREB1 bound to DJ-1 promoter and positively regulated its expression under both unstressed and 1-methyl-4-phenylpyridinium-induced oxidative stress conditions and that ChemJ promoted DJ-1 expression via activating PKA/CREB1 pathway in SH-SY5Y cells. Our results demonstrated that ChemJ alleviated the MPP+-induced oxidative stress through a PKA/CREB1-mediated regulation of DJ-1 expression, thus offering a novel and promising avenue for PD treatment.

Microglial Activation Imaging Using 18F-DPA-714 PET/MRI for Detecting Autoimmune Encephalitis.

Background Translocator protein (TSPO) PET has been used to visualize microglial activation in neuroinflammation and is a potential imaging tool for detecting autoimmune encephalitis (AIE). Purpose To compare the detection rate between TSPO radioligand fluorine 18 (18F) DPA-714 PET and conventional MRI and assess the relationship between 18F-DPA-714 uptake and clinical features in participants with AIE. Materials and Methods Healthy volunteers and patients with AIE were enrolled in this prospective study between December 2021 and April 2023. All participants underwent hybrid brain 18F-DPA-714 PET/MRI and antibody testing. Modified Rankin scale scoring and AIE-related symptoms were assessed in participants with AIE. Positive findings were defined as intensity of 18F-DPA-714 uptake above a threshold of the mean standardized uptake value ratio (SUVR) plus 2 SD inside the corresponding brain regions of healthy controls. The McNemar test was used to compare the positive detection rate between the two imaging modalities; the independent samples t test was used to compare continuous variables; and correlation with Bonferroni correction was used to assess the relationship between 18F-DPA-714 uptake and clinical features. Results A total of 25 participants with AIE (mean age, 39.24 years ± 19.03 [SD]) and 10 healthy controls (mean age, 28.70 years ± 5.14) were included. The positive detection rate of AIE was 72% (18 of 25) using 18F-DPA-714 PET compared to 44% (11 of 25) using conventional MRI, but the difference was not statistically significant (P = .065). Participants experiencing seizures exhibited significantly higher mean SUVR in the entire cortical region than those without seizures (1.23 ± 0.21 vs 1.15 ± 0.18; P = .003). Of the 13 participants with AIE who underwent follow-up PET/MRI, 11 (85%) demonstrated reduced uptake of 18F-DPA-714 accompanied by relief of symptoms after immunosuppressive treatment. Conclusion 18F-DPA-714 PET has potential value in supplementing MRI for AIE detection. Clinical trial registration no. NCT05293405 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Zaharchuk in this issue.

The regulation of NFKB1 on CD200R1 expression and their potential roles in Parkinson's disease.

BACKGROUND: Overactivated microglia are a key contributor to Parkinson's disease (PD) by inducing neuroinflammation. CD200R1, a membrane glycoprotein mainly found on microglia, is crucial for maintaining quiescence with its dysregulation linked to microglia's abnormal activation. We and other groups have reported a decline in CD200R1 levels in several neurological disorders including PD. However, the mechanism regulating CD200R1 expression and the specific reasons for its reduction in PD remain largely unexplored. Given the pivotal role of transcription factors in gene expression, this study aimed to elucidate the transcriptional regulation of CD200R1 and its implications in PD. METHODS: The CD200R1 promoter core region was identified via luciferase assays. Potential transcription factors were predicted using the UCSC ChIP-seq database and JASPAR. NFKB1 binding to the CD200R1 core promoter was substantiated through electrophoretic mobility shift and chromatin immunoprecipitation assays. Knocking-down or overexpressing NFKB1 validated its regulatory effect on CD200R1. Correlation between decreased CD200R1 and deficient NFKB1 was studied using Genotype-Tissue Expression database. The clinical samples of the peripheral blood mononuclear cells were acquired from 44 PD patients (mean age 64.13 ± 9.78, 43.2% male, median Hoehn-Yahr stage 1.77) and 45 controls (mean age 64.70 ± 9.41, 52.1% male). NFKB1 knockout mice were utilized to study the impact of NFKB1 on CD200R1 expression and to assess their roles in PD pathophysiology. RESULTS: The study identified the CD200R1 core promoter region, located 482 to 146 bp upstream of its translation initiation site, was directly regulated by NFKB1. Significant correlation between NFKB1 and CD200R1 expression was observed in human PMBCs. Both NFKB1 and CD200R1 were significantly decreased in PD patient samples. Furthermore, NFKB1-/- mice exhibited exacerbated microglia activation and dopaminergic neuron loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. CONCLUSION: Our study identified that NFKB1 served as a direct regulator of CD200R1. Reduced NFKB1 played a critical role in CD200R1 dysregulation and subsequent microglia overactivation in PD. These findings provide evidence that targeting the NFKB1-CD200R1 axis would be a novel therapeutic strategy for PD.

Nilotinib boosts the efficacy of anti-PDL1 therapy in colorectal cancer by restoring the expression of MHC-I.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs. METHODS: Dual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated. RESULTS: Nilotinib induces MHC-I expression in CRC cells, enhances CD8+ T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-κB pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects. CONCLUSION: This study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC.

Mycoplasma genitalium membrane lipoprotein induces GAPDH malonylation in urethral epithelial cells to regulate cytokine response.

Membrane lipoproteins serve as primary pro-inflammatory virulence factors in Mycoplasma genitalium. Membrane lipoproteins primarily induce inflammatory responses by activating Toll-like Receptor 2 (TLR2); however, the role of the metabolic status of urethral epithelial cells in inflammatory response remains unclear. In this study, we found that treatment of uroepithelial cell lines with M. genitalium membrane lipoprotein induced metabolic reprogramming, characterized by increased aerobic glycolysis, decreased oxidative phosphorylation, and increased production of the metabolic intermediates acetyl-CoA and malonyl-CoA. The metabolic shift induced by membrane lipoproteins is reversible upon blocking MyD88 and TRAM. Malonyl-CoA induces malonylation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and malonylated GAPDH could dissociate from the 3' untranslated region of TNF-α and IFN-γ mRNA. This dissociation greatly reduces the inhibitory effect on the translation of TNF-α and IFN-γ mRNA, thus achieving fine-tuning control over cytokine secretion. These findings suggest that GAPDH malonylation following M. genitalium infection is an important inflammatory signal that plays a crucial role in urogenital inflammatory diseases.

Genomic insights into local adaptation of upland cotton in China and Pakistan.

KEY MESSAGE: Different kinship and resistance to cotton leaf curl disease (CLCuD) and heat were found between upland cotton cultivars from China and Pakistan. 175 SNPs and 82 InDels loci related to yield, fiber quality, CLCuD, and heat resistance were identified. Elite alleles found in Pakistani accessions aided local adaptation to climatic condition of two countries. Adaptation of upland cotton (Gossypium hirsutum) beyond its center of origin is expected to be driven by tailoring of the genome and genes to enhance yield and quality in new ecological niches. Here, resequencing of 456 upland cotton accessions revealed two distinct kinships according to the associated country. Fiber quality and lint percentage were consistent across kinships, but resistance to cotton leaf curl disease (CLCuD) and heat was distinctly exhibited by accessions from Pakistan, illustrating highly local adaption. A total of 175 SNP and 82 InDel loci related to yield, fiber quality, CLCuD and heat resistance were identified; among them, only two overlapped between Pakistani and Chinese accessions underscoring the divergent domestication and improvement targets in each country. Loci associated with resistance alleles to leaf curl disease and high temperature were largely found in Pakistani accessions to counter these stresses prevalent in Pakistan. These results revealed that breeding activities led to the accumulation of unique alleles and helped upland cotton become adapted to the respective climatic conditions, which will contribute to elucidating the genetic mechanisms that underlie resilience traits and help develop climate-resilient cotton cultivars for use worldwide.

SRS 16-86 promotes diabetic nephropathy recovery by regulating ferroptosis.

Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM), and cell death plays an important role. Ferroptosis is a recently discovered type of iron-dependent cell death and one that is different from other kinds of cell death including apoptosis and necrosis. However, ferroptosis has not been described in the context of DN. This study explored the role of ferroptosis in DN pathophysiology and aimed to confirm the efficacy of the ferroptosis inhibitor SRS 16-86 on DN. Streptozotocin injection was used to establish the DM and DN animal models. To investigate the presence or occurrence of ferroptosis in DN, we assessed the concentrations of iron, reactive oxygen species and specific markers associated with ferroptosis in a rat model of DN. Additionally, we performed haematoxylin-eosin staining, blood biochemistry, urine biochemistry and kidney function analysis to evaluate the efficacy of the ferroptosis inhibitor SRS 16-86 in ameliorating DN. We found that SRS 16-86 could improve the recovery of renal function after DN by upregulating glutathione peroxidase 4, glutathione and system xc -light chain and by downregulating the lipid peroxidation markers and 4-hydroxynonenal. SRS 16-86 treatment could improve renal organization after DN. The inflammatory cytokines interleukin 1ß and tumour necrosis factor α and intercellular adhesion molecule 1 were significantly decreased following SRS 16-86 treatment after DN. The results indicate that there is a strong connection between ferroptosis and the pathological mechanism of DN. The efficacy of the ferroptosis inhibitor SRS 16-86 in DN repair supports its use as a new therapeutic treatment for DN.

MARK2 phosphorylates eIF2α in response to proteotoxic stress.

The regulation of protein synthesis is essential for maintaining cellular homeostasis, especially during stress responses, and its dysregulation could underlie the development of human diseases. The critical step during translation regulation is the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). Here we report the identification of a direct kinase of eIF2α, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2α in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2α kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKCδ), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKCδ are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKCδ-MARK2-eIF2α cascade that may play a critical role in cellular proteotoxic stress responses and human diseases.

Contrasting presentations of children with ADHD and subthreshold ADHD.

BACKGROUND: We aimed to explore the differences and relationships in body composition, social function, and comorbidities between children with attention-deficit/hyperactivity disorder (ADHD) and subthreshold ADHD. METHODS: A case-control study was conducted to analyze the differences between children with ADHD and subthreshold ADHD. Logistic regression models were used to analyze the factors influencing social functional impairments and comorbidities. RESULTS: Children with ADHD and subthreshold ADHD had a higher fat mass index than healthy children (p < 0.05). The scores of all six social functional domains were higher in the subthreshold ADHD and ADHD groups than in the control group (p < 0.05). The prevalence of comorbidity was higher in children with subthreshold ADHD and ADHD compared to the control group (p < 0.05). Inattention and comorbid anxiety/depression increased the risk of functional impairments in children with ADHD (full syndrome/subthreshold), whereas a higher fat-free mass index reduced the risk. The severity of hyperactivity was associated with a higher risk of comorbidity in children with ADHD (full syndrome/subthreshold). CONCLUSION: Children with subthreshold ADHD and ADHD had more fat mass and higher rates of social functional impairments and comorbidities than healthy children. There were clinical correlations between body composition, social functional impairments, and comorbidities in ADHD. IMPACT: 1. Children with subthreshold ADHD and ADHD had higher fat mass levels than normal children. 2. The social function impairments and comorbidities of children with subthreshold ADHD were similar to those with ADHD. 3. Inattentiveness and anxiety/depression increased the risk of functional impairments in children with ADHD (full syndrome/subthreshold), while a higher fat-free mass index and skeletal muscle-to-body fat ratio reduced the risk.

The ZDHHC13/ZDHHC17 subfamily: from biological functions to therapeutic targets of diseases.

The ZDHHC13/ZDHHC17 subfamily belongs to the zinc finger DHHC-domain containing (ZDHHC) family, including ZDHHC13 and ZDHHC17. Recent studies have shown that the ZDHHC13/ZDHHC17 subfamily is involved in various pathological and physiological processes, including S-palmitoylation, Mg2+ transport, and CALCOCO1-mediated Golgiphagy. Moreover, the ZDHHC13/ZDHHC17 subfamily plays a crucial role in the occurrence and development of many diseases, including Huntington disease (HD), osteoporosis, atopic dermatitis, diabetes, and cancer. In the present review, we describe the distribution, structure, and post-translational modifications (PTMs) of the ZDHHC13/ZDHHC17 subfamily. Moreover, we effectively summarize the biological functions and associated diseases of this subfamily. Given the pleiotropy of the ZDHHC13/ZDHHC17 subfamily, it is imperative to conduct further research on its members to comprehend the pertinent pathophysiological mechanisms and to devise tactics for managing and controlling various diseases.

Potential optimized route for mesenchymal stem cell transplantation in a rat model of cerebral palsy.

Cerebral palsy (CP) is a movement and posture disorder that affects over 50 million people worldwide. Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation has emerged as an attractive therapeutic strategy for CP. The administration route appears to be crucial for hUC-MSC to provide adequate neuroprotection. Wistar rats were given hypoxia-ischemia to make the CP model on postnatal day 5. On postnatal day 21, DiR-labeled hUC-MSC were transplanted into the CP rats by intravenous, intrathecal, and lateral ventricle for cell tracking. Uninfused CP rats served as the negative control. The motor behavioral and pathological alteration was analyzed 11, 25, and 39 days after transplantation to assess motor function, immune inflammation, neurotrophy, and endogenous repair. In vivo imaging tracking techniques revealed that intravenous infusion resulted in fewer transplanted cells in the target brain than intrathecal and lateral ventricle infusion (p＜0.05). Three different routes of hUC-MSC infusion improved the motor function of CP rats (p＜0.05). At 11 days post-infusion, intrathecal infusion outperformed intravenous with a significant neurotrophic and oligodendrocyte maturation effect (p＜0.05). Intrathecal infusion equaled lateral ventricle infusion after 25 days. At 39 days post-infusion, lateral ventricle infusion exceeded intravenous and intrathecal infusion with a significant immunosuppressive effect (p＜0.05). Considering the improved effect and less trauma shown early in the intrathecal infusion, repeated intrathecal administration may ultimately lead to the greatest benefit.

Relationship between ischemic index, leakage index, and macular edema in branch retinal vein occlusion.

PURPOSE: To investigate the combined association of the ischemic index and leakage index with macular edema on ultra-widefield fluorescein angiography (UWFFA) in patients with branch retinal vein occlusion (BRVO). METHODS: Retrospective image analysis study. The leakage index and ischemic index were calculated using Fiji after aligning early and late UWFFA images. Differences in the ischemic index, leakage index, and central macular thickness (CMT) between ischemic and non-ischemic BRVO were compared. Moreover, the association between the ischemic index, leakage index, and macular edema was analyzed. RESULTS: Eighty-three patients with BRVO were enrolled, including 53 non-ischemic BRVO and 30 ischemic BRVO patients. No significant differences were observed in leakage index and CMT between ischemic BRVO and non-ischemic BRVO (all P > 0.05). In all included patients, CMT correlated with the panretina and all subregion leakage indexes (all P < 0.01), but not with the ischemic index (all P > 0.05). In the ischemic BRVO group, CMT showed a correlation with the leakage index in several regions, but not with the ischemic index. After adjusting for the ischemic index and other clinical features, CMT remained significantly correlated with the leakage index in all regions. CONCLUSION: The leakage index may be a more effective biomarker for monitoring BRVO-associated macular edema compared to the ischemic index. Further follow-up studies are warranted to validate these findings.

RELATIONSHIP BETWEEN RETINAL HEMORRHAGE ON GREEN AND RED CHANNELS OF ULTRA-WIDEFIELD FUNDUS IMAGES AND RETINAL PERFUSION IN ACUTE BRANCH RETINAL VEIN OCCLUSION.

PURPOSE: To explore the relationship between retinal hemorrhage in the green and red channels on ultra-widefield fundus images and the nonperfusion area (NPA) on ultra-widefield fundus fluorescein angiography in patients with acute branch retinal vein occlusion (BRVO). METHODS: This was a retrospective cross-sectional study with 96 patients, including 46 with ischemic BRVO and 50 with nonischemic BRVO. Correlation analysis between green channel hemorrhage (GCH), red channel hemorrhage (RCH), and NPA was performed. Panretina was divided into posterior and peripheral areas. RESULTS: Ischemic BRVO showed significantly higher GCH% and RCH% than nonischemic BRVO in the peripheral regions (both P < 0.001), whereas no significant differences were observed in the panretinal and posterior areas (all P > 0.05). Significant correlations were found between NPA% in the panretinal and peripheral areas and the corresponding GCH% and RCH% (all P < 0.01). However, no significant correlation was observed between posterior NPA% and posterior GCH% or RCH% (both P > 0.05). In addition, peripheral GCH% and RCH% were related to panretinal NPA% (r = 0.506, P < 0.001; r = 0.558, P < 0.001). CONCLUSION: Retinal hemorrhage on ultra-widefield fundus image was significantly associated with NPA, providing insights for assessing retinal perfusion status in acute BRVO patients.

Association between new Life's Essential 8 and the risk of all-cause and cardiovascular mortality in patients with hypertension: a cohort study.

BACKGROUND: The American Heart Association recently introduced a new model for cardiovascular health (CVH) known as Life's Essential 8 (LE8). The impact of LE8 on hypertensive individuals is currently unclear. In our study, we investigated the correlation between comprehensive and individual CVH indicators as defined by LE8, and the mortality rates in hypertension patients. METHODS: We analyzed a total of 8,448 hypertensive individuals aged ≥ 20 years who participated in the National Health and Nutrition Examination Survey from 2007 to 2016. These participants were nonpregnant and noninstitutionalized. We identified their mortality by linking their data to the National Death Index until December 31, 2019. The overall cardiovascular health (CVH) was assessed using the LE8 score, which ranged from 0 to 100. Additionally, we evaluated the scores for each component of diet, physical activity, tobacco/nicotine exposure, sleep duration, body mass index, non-high-density lipoprotein cholesterol, blood glucose, and blood pressure. The CVH were categorized into low (0-49), moderate (50-79), and high (80-100) CVH. RESULTS: Over an average follow-up period of 7.41 years, 1,482 (17.54%) of the participants died, among which 472 deaths were attributed to CVD. When compared to adults with lower total CVH scores, those with elevated total CVH scores displayed a 37% reduced risk of mortality from all causes (adjusted hazard ratio [aHR] = 0.63, 95% confidence interval [CI] = 0.45-0.88). In relation to CVD-specific mortality, the corresponding aHRs for moderate and high total CVH scores were 0.76 (0.60-0.97) and 0.54 (0.31-0.94), respectively. Furthermore, after adjusting for potential confounders, it was observed that higher scores on the LE8 index were associated with a reduced risk of both all-cause mortality (aHR for every 10-score increase, 0.91; 95% CI = 0.86-0.96) and CVD-specific mortality (aHR for every 10-score increase, 0.82; 95% CI = 0.75-0.90). Notably, a linear dose-response relationship was observed in this association. Similar patterns were identified in the relationship between health behavior and both all-cause and CVD-specific mortality. CONCLUSIONS: Achieving a higher CVH score, as per the new LE8 guidelines, has been found to be associated with a reduced risk of mortality from all causes and specifically from CVD in patients with hypertension. Therefore, public health and healthcare initiatives that focus on promoting higher CVH scores could potentially yield significant benefits in terms of reducing mortality rates among individuals with hypertension.

Placental growth factor alleviates hyperglycemia-induced trophoblast pyroptosis by regulating mitophagy.

INTRODUCTION: Hyperglycemia is closely related to trophoblast dysfunction during pregnancy and results in suppressed invasion, migration, and pro-inflammatory cell death of trophoblasts. Hyperglycemia is a dependent risk factor for gestational hypertension accompanied by decreased placental growth factor (PLGF), which is important for maternal and fetal development. However, there is currently a lack of evidence to support whether PLGF can alleviate trophoblast cell dysfunction caused by high blood sugar. Here, we aim to clarify the effect of hyperglycemia on trophoblast dysfunction and determine how PLGF affects this process. METHODS: The changes in placental tissue histomorphology from gestational diabetes mellitus (GDM) patients were compared with those of normal placentas. HTR8/SVneo cells were cultured in different amounts of glucose to examine cellular pyroptosis, migration, and invasion as well as PLGF levels. Furthermore, the levels of pyroptosis-related proteins (NLRP3, pro-caspase1, caspase1, IL-1ß, and Gasdermin D [GSDMD]) as well as autophagy-related proteins (LC3-II, Beclin1, and p62) were examined by Western blotting. The GFP-mRFP-LC3-II system and transmission electron microscopy were used to detect mitophagy levels, and small interfering RNAs targeting BCL2 Interacting Protein 3 (siBNIP3) and PTEN-induced kinase 1 (siPINK1) were used to determine the role of mitophagy in pyroptotic death of HTR-8/SVneo cells. RESULTS: Our results show that hyperglycemia upregulates NLRP3, pro-caspase1, caspase1, IL-1ß at the protein level in GDM patients. High glucose (HG, 25 mM) inhibits viability, invasion, and migration of trophoblast cells while suppressing superoxide dismutase levels and promoting malondialdehyde production, thus leading to a senescence associated beta-gal-positive cell burst. PLGF levels in nucleus and the cytosol are also inhibited by HG, whereas PLGF treatment inhibited pyroptosis-related protein levels of NLRP3, pro-caspase1, caspase1, IL-1ß, and GSDMD, Gasdermin D N-terminal domain (GSDMD-N). HG-induced mitochondrial dysfunction and BNIP3 and PINK1/Parkin expression. Knocking down BINP3 and PINK1 abolished the protective role of PLGF by preventing mitophagy. CONCLUSION: PLGF inhibited hyperglycemia, while PLGF reversed hyperglycemic injury by promoting mitophagy via the BNIP3/PINK1/Parkin pathway. Altogether, these results suggest that PLGF may protect against trophoblast dysfunction in diabetes.

New wheat straw fermentation feed: recombinant Schizosaccharomyces pombe efficient degradation of lignocellulose and increase feed protein.

Wheat straw contains a high amount of lignin, hindering the action of cellulase and hemicellulase enzymes, leading to difficulties in nutrient absorption by animals from straw feed. However, currently, the biological treatment of straw relies primarily on fungal degradation and cannot be directly utilized for the preparation of livestock feed. This study focuses on enzymatic co-fermentation of wheat straw to produce high-protein, low-cellulose biological feed, integrating lignin degradation with feed manufacturing, thereby simplifying the feed production process. After the optimization using Box-Behnken Design for the feed formulation, with a glucose oxidase addition of 2.46%, laccase addition of 3.4%, and malonic acid addition of 0.6%, the wheat straw feed prepared in this experiment exhibited a true protein content of 9.35%. This represented a fourfold increase compared to the non-fermented state, and the lignocellulose degradation rate of wheat straw reached 45.42%. These results not only highlight the substantial enhancement in protein content but also underscore the significant advancement in lignocellulose breakdown. This formulation significantly enhanced the palatability and nutritional value of the straw feed, contributing to the industrial development of straw feed.

Identification of candidate genes in cotton associated with specific seed traits and their initial functional characterization in Arabidopsis.

Oilseed crops are used to produce vegetable oil to satisfy the requirements of humans and livestock. Cotton (Gossypium spp.) is of great economic value because it is used as both an important textile commodity and a nutrient-rich resource. Cottonseed oil is rich in polyunsaturated fatty acids and does not contain trans fatty acids; hence, it is considered a healthy vegetable oil. However, research on the genetic basis for cottonseed protein content, oil production, and fatty acid composition is lacking. Here, we investigated the protein content, oil content, and fatty acid composition in terms of oleic acid (C18:1) and linoleic acid (C18:2) in mature cottonseeds from 318 Gossypium hirsutum accessions. Moreover, we examined the dynamic change of protein content and lipid composition including palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2), and linolenic acid (C18:3) in developing seeds from 258 accessions at 10 and 20 days post-anthesis. Then, we conducted a genome-wide association study and identified 152 trait-associated loci and 64 candidate genes responsible for protein and oil-related contents in mature cottonseeds and ovules. Finally, six candidate genes were experimentally validated to be involved in the regulation of fatty acid biosynthesis through heterologous expression in Arabidopsis. These results comprise a solid foundation for expanding our understanding of lipid biosynthesis in cotton, which will help breeders manipulate protein and oil contents to make it a fully developed 'fiber, food, and oil crop'.

Elabela-apelin-12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1-P2X7 signaling pathway.

The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela-apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin-12, -17, and -36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)-P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela- and apelin isoforms-induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti-HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib-induced zebrafish trunk model. Overall, the elabela-apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1-P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.