Arabidopsis class A S-acyl transferases modify the pollen receptors LIP1 and PRK1 to regulate pollen tube guidance.

Protein S-acylation catalyzed by protein S-acyl transferases (PATs) is a reversible lipid modification regulating protein targeting, stability, and interaction profiles. PATs are encoded by large gene families in plants, and many proteins including receptor-like cytoplasmic kinases (RLCKs) and receptor-like kinases (RLKs) are subject to S-acylation. However, few PATs have been assigned substrates, and few S-acylated proteins have known upstream enzymes. We report that Arabidopsis (Arabidopsis thaliana) class A PATs redundantly mediate pollen tube guidance and participate in the S-acylation of POLLEN RECEPTOR KINASE1 (PRK1) and LOST IN POLLEN TUBE GUIDANCE1 (LIP1), a critical RLK or RLCK for pollen tube guidance, respectively. PAT1, PAT2, PAT3, PAT4, and PAT8, collectively named PENTAPAT for simplicity, are enriched in pollen and show similar subcellular distribution. Functional loss of PENTAPAT reduces seed set due to male gametophytic defects. Specifically, pentapat pollen tubes are compromised in directional growth. We determine that PRK1 and LIP1 interact with PENTAPAT, and their S-acylation is reduced in pentapat pollen. The plasma membrane (PM) association of LIP1 is reduced in pentapat pollen, whereas point mutations reducing PRK1 S-acylation affect its affinity with its interacting proteins. Our results suggest a key role of S-acylation in pollen tube guidance through modulating PM receptor complexes.

Running exercise alleviates hippocampal neuroinflammation and shifts the balance of microglial M1/M2 polarization through adiponectin/AdipoR1 pathway activation in mice exposed to chronic unpredictable stress.

Running exercise has been shown to alleviate depressive symptoms. However, the mechanism underlying the antidepressant effects of running exercise is not fully understood. The imbalance of M1/M2 microglia phenotype/polarization and concomitant dysregulation of neuroinflammation play crucial roles in the pathogenesis of depression. Running exercise increases circulating levels of adiponectin which is known to cross the blood‒brain barrier and suppress inflammatory responses. AdipoR1 is an adiponectin receptor that is involved in regulating microglial phenotypes and activation states. However, whether running exercise regulates hippocampal microglial phenotypes and neuroinflammation through adiponectin/AdipoR1 to exert its antidepressant effects remains unclear. In the current study, 4 weeks of running exercise significantly alleviated the depressive-like behaviors of chronic unpredictable stress (CUS)-exposed mice. Moreover, running exercise decreased the microglial numbers and altered microglial morphology in three subregions of the hippocampus to restore the M1/M2 balance; these effects were accompanied by regulation of pro-/anti-inflammatory cytokine production and secretion in CUS-exposed mice. These effects may involve elevation of peripheral tissue (adipose tissue and muscle) and plasma adiponectin levels, and hippocampal AdipoR1 levels as well as activation of the AMPK-NF-κB/STAT3 signaling pathway by running exercise. When an adeno-associated virus was used to knock down hippocampal AdipoR1, mice showed depressive-like behaviors and alterations in microglia and inflammatory factor expression in the hippocampus that were similar to those observed in CUS-exposed mice. Together, these results suggest that running exercise maintains the M1/M2 balance and inhibits neuroinflammation in the hippocampus of CUS-exposed mice. These effects might occur via adiponectin/AdipoR1-mediated activation of the AMPK-NF-κB/STAT3 signaling pathway.

The distinct initiation sites and processing activities of TTLL4 and TTLL7 in glutamylation of brain tubulin.

Mammalian brain tubulins undergo a reversible posttranslational modification-polyglutamylation-which attaches a secondary polyglutamate chain to the primary sequence of proteins. Loss of its erasers can disrupt polyglutamylation homeostasis and cause neurodegeneration. Tubulin tyrosine ligase like 4 (TTLL4) and TTLL7 were known to modify tubulins, both with preference for the ß-isoform, but differently contribute to neurodegeneration. However, differences in their biochemical properties and functions remain largely unknown. Here, using an antibody-based method, we characterized the properties of a purified recombinant TTLL4 and confirmed its sole role as an initiator, unlike TTLL7, which both initiates and elongates the side chains. Unexpectedly, TTLL4 produced stronger glutamylation immunosignals for α-isoform than ß-isoform in brain tubulins. Contrarily, the recombinant TTLL7 raised comparable glutamylation immunoreactivity for two isoforms. Given the site selectivity of the glutamylation antibody, we analyzed modification sites of two enzymes. Tandem mass spectrometry analysis revealed their incompatible site selectivity on synthetic peptides mimicking carboxyl termini of α1- and ß2-tubulins and a recombinant tubulin. Particularly, in the recombinant α1A-tubulin, a novel region was found glutamylated by TTLL4 and TTLL7, that again at distinct sites. These results pinpoint different site specificities between two enzymes. Moreover, TTLL7 exhibits less efficiency to elongate microtubules premodified by TTLL4, suggesting possible regulation of TTLL7 elongation activity by TTLL4-initiated sites. Finally, we showed that kinesin behaves differentially on microtubules modified by two enzymes. This study underpins the different reactivity, site selectivity, and function of TTLL4 and TTLL7 on brain tubulins and sheds light on their distinct role in vivo.

Arabidopsis Sar1b is critical for pollen tube growth.

Pollen tube growth is an essential step leading to reproductive success in flowering plants, in which vesicular trafficking plays a key role. Vesicular trafficking from endoplasmic reticulum to the Golgi apparatus is mediated by the coat protein complex II (COPII). A key component of COPII is small GTPase Sar1. Five Sar1 isoforms are encoded in the Arabidopsis genome and they show distinct while redundant roles in various cellular and developmental processes, especially in reproduction. Arabidopsis Sar1b is essential for sporophytic control of pollen development while Sar1b and Sar1c are critical for gametophytic control of pollen development. Because functional loss of Sar1b and Sar1c resulted in pollen abortion, whether they influence pollen tube growth was unclear. Here we demonstrate that Sar1b mediates pollen tube growth, in addition to its role in pollen development. Although functional loss of Sar1b does not affect pollen germination, it causes a significant reduction in male transmission and of pollen tube penetration of style. We further show that membrane dynamics at the apex of pollen tubes are compromised by Sar1b loss-of-function. Results presented provide further support of functional complexity of the Sar1 isoforms.

Dulaglutide restores endothelial progenitor cell levels in diabetic mice and mitigates high glucose-induced endothelial injury through SIRT1-mediated mitochondrial fission.

Type 2 diabetes mellitus (T2DM) significantly impairs the functionality and number of endothelial progenitor cells (EPCs) and resident endothelial cells, critical for vascular repair and regeneration, exacerbating the risk of vascular complications. GLP-1 receptor agonists, like dulaglutide, have emerged as promising therapeutic agents due to their multifaceted effects, including the enhancement of EPC activity and protection of endothelial cells. This study investigates dulaglutide's effects on peripheral blood levels of CD34+ and CD133+ cells in a mouse model of lower limb ischemia and its protective mechanisms against high-glucose-induced damage in endothelial cells. Results demonstrated that dulaglutide significantly improves blood flow, reduces tissue damage and inflammation in ischemic limbs, and enhances glycemic control. Furthermore, dulaglutide alleviated high-glucose-induced endothelial cell damage, evident from improved tube formation, reduced reactive oxygen species accumulation, and restored endothelial junction integrity. Mechanistically, dulaglutide mitigated mitochondrial fission in endothelial cells under high-glucose conditions, partly through maintaining SIRT1 expression, which is crucial for mitochondrial dynamics. This study reveals the potential of dulaglutide as a therapeutic option for vascular complications in T2DM patients, highlighting its role in improving endothelial function and mitochondrial integrity.

RHO OF PLANT proteins are essential for pollen germination in Arabidopsis.

Pollen germination is a process of polarity establishment, through which a single and unique growth axis is established. Although most of the intracellular activities associated with pollen germination are controlled by RHO OF PLANTs (ROPs) and increased ROP activation accompanies pollen germination, a critical role of ROPs in this process has not yet been demonstrated. Here, by genomic editing of all 4 Arabidopsis (Arabidopsis thaliana) ROPs that are preferentially expressed in pollen, we showed that ROPs are essential for polarity establishment during pollen germination. We further identified and characterized 2 ROP effectors in pollen germination (REGs) through genome-wide interactor screening, boundary of ROP domain (BDR) members BDR8 and BDR9, whose functional loss also resulted in no pollen germination. BDR8 and BDR9 were distributed in the cytosol and the vegetative nucleus of mature pollen grains but redistributed to the plasma membrane (PM) of the germination site and to the apical PM of growing pollen tubes. We demonstrated that the PM redistribution of BDR8 and BDR9 during pollen germination relies on ROPs but not vice versa. Furthermore, enhanced expression of BDR8 partially restored germination of rop1 pollen but had no effects on that of the quadruple rop pollen, supporting their genetic epistasis. Results presented here demonstrate an ROP signaling route essential for pollen germination, which supports evolutionarily conserved roles of Rho GTPases in polarity establishment.

Stress response membrane protein OsSMP2 negatively regulates rice tolerance to drought.

In a gene chip analysis, rice (Oryza sativa) OsSMP2 gene expression was induced under various abiotic stresses, prompting an investigation into its role in drought resistance and abscisic acid signaling. Subsequent experiments, including qRT-PCR and ß-glucuronidase activity detection, affirmed the OsSMP2 gene's predominant induction by drought stress. Subcellular localization experiments indicated the OsSMP2 protein primarily localizes to the cell membrane system. Overexpressing OsSMP2 increased sensitivity to exogenous abscisic acid, reducing drought resistance and leading to reactive oxygen species accumulation under drought stress. Conversely, in simulated drought experiments, OsSMP2-silenced transgenic plants showed significantly longer roots compared with the wild-type Nipponbare. These results suggest that OsSMP2 overexpression negatively affects rice drought resistance, offering valuable insights into molecular mechanisms, and highlight OsSMP2 as a potential target for enhancing crop resilience to drought stress.

Net greenhouse gas balance in U.S. croplands: How can soils be part of the climate solution?

Agricultural soils play a dual role in regulating the Earth's climate by releasing or sequestering carbon dioxide (CO2 ) in soil organic carbon (SOC) and emitting non-CO2 greenhouse gases (GHGs) such as nitrous oxide (N2 O) and methane (CH4 ). To understand how agricultural soils can play a role in climate solutions requires a comprehensive assessment of net soil GHG balance (i.e., sum of SOC-sequestered CO2 and non-CO2 GHG emissions) and the underlying controls. Herein, we used a model-data integration approach to understand and quantify how natural and anthropogenic factors have affected the magnitude and spatiotemporal variations of the net soil GHG balance in U.S. croplands during 1960-2018. Specifically, we used the dynamic land ecosystem model for regional simulations and used field observations of SOC sequestration rates and N2 O and CH4 emissions to calibrate, validate, and corroborate model simulations. Results show that U.S. agricultural soils sequestered 13.2 ± 1.16 $$ 13.2\pm 1.16 $$ Tg CO2 -C year-1 in SOC (at a depth of 3.5 m) during 1960-2018 and emitted 0.39 ± 0.02 $$ 0.39\pm 0.02 $$ Tg N2 O-N year-1 and 0.21 ± 0.01 $$ 0.21\pm 0.01 $$ Tg CH4 -C year-1 , respectively. Based on the GWP100 metric (global warming potential on a 100-year time horizon), the estimated national net GHG emission rate from agricultural soils was 122.3 ± 11.46 $$ 122.3\pm 11.46 $$ Tg CO2 -eq year-1 , with the largest contribution from N2 O emissions. The sequestered SOC offset ~28% of the climate-warming effects resulting from non-CO2 GHG emissions, and this offsetting effect increased over time. Increased nitrogen fertilizer use was the dominant factor contributing to the increase in net GHG emissions during 1960-2018, explaining ~47% of total changes. In contrast, reduced cropland area, the adoption of agricultural conservation practices (e.g., reduced tillage), and rising atmospheric CO2 levels attenuated net GHG emissions from U.S. croplands. Improving management practices to mitigate N2 O emissions represents the biggest opportunity for achieving net-zero emissions in U.S. croplands. Our study highlights the importance of concurrently quantifying SOC-sequestered CO2 and non-CO2 GHG emissions for developing effective agricultural climate change mitigation measures.

The efficacy and safety of vincristine, irinotecan and anlotinib in Epithelioid Sarcoma.

BACKGROUND: Epithelioid sarcoma is a rare soft tissue sarcoma characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied the effects of irinotecan-based chemotherapy in a series of epithelioid sarcoma patients. METHODS: We retrospectively reviewed data from patients with metastatic or unresectable epithelioid sarcoma at the Peking University People's Hospital treated with irinotecan (50 mg/m2/d d1-5 Q3W) in combination with Anlotinib (12 mg Qd, 2 weeks on and 1 week off) from July 2015 to November 2021. RESULTS: A total of 54 courses were administered. With a median follow up of 21.2 months (95% CI, 12.2, 68.1), the 5-year overall survival rate was 83.3%. Five of eight (62.5%) patients presented with unresectable localized lesions, including local tumor thrombosis and lymphatic metastasis. The other patients had unresectable pulmonary metastases. Six of eight (75%) patients had progressed following two lines of systemic therapy. The objective response rate reached 37.5% (three of eight patients) while stabilized disease was observed in 62.5% (five of eight) of patients. No patient had progressed at initial evaluation. At the last follow up, two patients were still using the combination and three patients had ceased the therapy due to toxicities such as diarrhea, nausea, and emesis. One patient changed to tazemetostat for maintenance and one patient stopped treatment due to coronavirus disease 2019 (COVID-19). Another patient stopped therapy as residual lesions had been radiated. CONCLUSIONS: The combination of irinotecan and Anlotinib as a salvage regimen may be considered another effective treatment option for refractory epithelioid sarcoma. TRIAL REGISTRATION: This study was approved in the Medical Ethics Committee of Peking University People's Hospital on October 28, 2022 (No.: 2022PHD015-002). The study was registered in Clinicaltrials.gov with identifier no. NCT05656222.

Gas-Responsive and Gas-Releasing Polymer Assemblies.

In order to explore the unique physiological roles of gas signaling molecules and gasotransmitters in vivo, chemists have engineered a variety of gas-responsive polymers that can monitor their changes in cellular milieu, and gas-releasing polymers that can orchestrate the release of gases. These have advanced their potential applications in the field of bio-imaging, nanodelivery, and theranostics. Since these polymers are of different chain structures and properties, the morphology of their assemblies will manifest distinct transitions after responding to gas or releasing gas. In this review, we summarize the fundamental design rationale of gas-responsive and gas-releasing polymers in structure and their controlled transition in self-assembled morphology and function, as well as present some perspectives in this prosperous field. Emerging challenges faced for the future research are also discussed.

Transfer of miR-877-3p via extracellular vesicles derived from dental pulp stem cells attenuates neuronal apoptosis and facilitates early neurological functional recovery after cerebral ischemia-reperfusion injury through the Bclaf1/P53 signaling pathway.

Cerebral ischemia-reperfusion injury (I/RI) is one of the principal pathogenic factors in the poor prognosis of ischemic stroke, for which current therapeutic options to enhance neurological recovery are notably insufficient. Dental pulp stem cell-derived extracellular vesicles (DPSC-EVs) have promising prospects in stroke treatment and the specific underlying mechanisms have yet to be fully elucidated. The present study observed that DPSC-EVs ameliorated the degree of cerebral edema and infarct volume by reducing the apoptosis of neurons. Furthermore, the miRNA sequencing and functional enrichment analysis identified that miR-877-3p as a key component in DPSC-EVs, contributing to neuroprotection and anti-apoptotic effects. Following target prediction and dual-luciferase assay indicated that miR-877-3p interacted with Bcl-2-associated transcription factor (Bclaf1) to play a function. The miR-877-3p inhibitor or Bclaf1 overexpression reversed the neuroprotective effects of DPSC-EVs. The findings reveal a novel therapeutic pathway where miR-877-3p, transferred via DPSC-EVs, confers neuroprotection against cerebral I/RI, highlighting its potential in promoting neuronal survival and recovery post-ischemia.

Electrochemical Synthesis of Selenosulfonates from Diselenides and Sulfonyl Hydrazides.

The electrochemical oxidative radical-radical cross-coupling of sulfonyl hydrazides with diselenides for the synthesis of selenosulfonates was successfully accomplished. The method is applicable to a wide range of aromatic/aliphatic sulfonyl hydrazides and diselenides, providing products in good to excellent yields. Notably, this protocol stands out for its green and sustainable nature, as it does not rely on transition metals and oxidizing agents, and the starting materials are cost-effective and readily available.

Novel ratio-expressions of genes enables estimation of wound age in contused skeletal muscle.

Given that combination with multiple biomarkers may well raise the predictive value of wound age, it appears critically essential to identify new features under the limited cost. For this purpose, the present study explored whether the gene expression ratios provide unique time information as an additional indicator for wound age estimation not requiring the detection of new biomarkers and allowing full use of the available data. The expression levels of four wound-healing genes (Arid5a, Ier3, Stom, and Lcp1) were detected by real-time polymerase chain reaction, and a total of six expression ratios were calculated among these four genes. The results showed that the expression levels of four genes and six ratios of expression changed time-dependent during wound repair. The six expression ratios provided additional temporal information, distinct from the four genes analyzed separately by principal component analysis. The overall performance metrics for cross-validation and external validation of four typical prediction models were improved when six ratios of expression were added as additional input variables. Overall, expression ratios among genes provide temporal information and have excellent potential as predictive markers for wound age estimation. Combining the expression levels of genes with ratio-expression of genes may allow for more accurate estimates of the time of injury.

Maternal body mass index and cerebral palsy in children: A systematic review and dose-response meta-analysis.

BACKGROUND: Accumulating studies indicate that maternal obesity is associated with the risk of cerebral palsy (CP); however, their conclusions have been inconsistent. OBJECTIVES: To quantitatively estimate the association between maternal body mass index (BMI) and CP in offspring. DATA SOURCES: PubMed, Embase and Web of Science. STUDY SELECTION AND DATA EXTRACTION: Articles published up to 18 September 2022 were searched that reported the correlation between maternal BMI and CP in children. Two reviewers independently extracted data and critically assessed articles. SYNTHESIS: Pooled relative risks (RR) and 95% confidence intervals (CI) were estimated by the random-effects model. Subgroup analysis and meta-regression were performed to explore sources of heterogeneity. RESULTS: In total, 11 articles (8,407,668 participants) were identified for inclusion in our meta-analysis. For maternal underweight, no significant association was found with CP risk (RR 1.11, 95% CI 0.90, 1.38). The risk of CP was increased by 25% (RR 1.25, 95% CI 1.06, 1.47), 38% (RR 1.38, 95% CI 1.18, 1.61) and 127% (RR 2.27, 95% CI 1.82, 2.83) for maternal overweight, obesity and obesity grade 3, respectively. In addition, we observed a positive linear dose-response relationship, with the pooled risk of cerebral palsy in offspring increasing by 3% with each unit increase in maternal BMI. CONCLUSION: This meta-analysis indicates that the risk of CP in offspring grew with maternal overweight or obesity grades increasing, and was positively correlated with maternal BMI.

Braden score can independently predict 90-day mortality in critically ill patients with dementia.

BACKGROUND: Dementia is a significant cause of death in the older population and is becoming an important public health issue as the population ages and the prevalence of dementia increases. The Braden score is one of the most commonly used clinical tools to assess the risk of skin pressure injury in patients, and some studies have reported that it may reflect the state of frailty of patients. The present study attempted to explore the association between Braden score and 90-day mortality, pressure injury, and aspiration pneumonia in older patients with dementia in the intensive care unit (ICU). METHODS: The study involved extracting crucial data from the Medical Information Market for Intensive Care IV (MIMIC-IV) database using Structured Query Language, with a license certificate obtained after completing the necessary training and examination available on the MIMIC-IV website. A retrospective analysis was performed on older patients with dementia, aged 65 or older, who were first admitted to the ICU. Ninth and tenth revision International Classification of Diseases codes were used to identify patients with dementia. The primary outcome was 90-day mortality. Cox proportional hazards models were used to determine the association between Braden score and death, and hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Propensity score matching and E-value assessments were employed for sensitivity analysis. RESULTS: A total of 2892 patients with a median age of approximately 85 years (interquartile range 78.74-89.59) were included, of whom 1625 were female (56.2%). Patients had a median Braden score of 14 (interquartile range 12-15) at ICU admission. Braden score at ICU admission was inversely associated with 90-day mortality risk after adjustment for demographics, severity of illness, treatment and medications, delirium, and sepsis (adjusted HR: 0.92, 95% CI: 0.87-0.98, p = 0.006). Patients were divided into two groups with a cut-off value of 15: high-risk group and low-risk group. Compared to the low-risk group (Braden score >15), the risk of 90-day mortality was significantly increased in the high-risk group (Braden score ≤15) (adjusted HR: 1.52, 95% CI: 1.10-2.09, p = 0.011, E-value: 2.01), the risk of pressure injury (adjusted OR: 2.62, 95% CI: 2.02-3.43, E-value: 2.62) and aspiration pneumonia (adjusted OR: 2.55, 95% CI: 1.84-3.61, E-value: 2.57) was also significantly higher. CONCLUSIONS: The Braden score may be a quick and simple screening tool to identify the risk of adverse outcomes in critically ill older adults with dementia.

Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway.

BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Dibenzofurans from nature: Biosynthesis, structural diversity, sources, and bioactivities.

Dibenzofurans are a small class of natural products with versatile biological activities that used to be thought to come mainly from lichens and ascomycetes. In fact, they are also distributed widely in higher plants, especially in the families Rosaceae and Myrtaceae. Dibenzofurans and derivatives from lichens and ascomycetes have been well reviewed, but dibenzofurans from all biological sources in nature have not been reviewed. In this review, dibenzofurans from all natural sources have been comprehensively reviewed, and a total of 211 dibenzofurans isolated and identified from organisms between 1843 and March 2023 are categorized and discussed, including their biosynthesis, structural diversity, sources, and bioactivities.

Evaluation of a biomarker (NO) dynamics in inflammatory zebrafish and periodontitis saliva samples via a fast-response and sensitive fluorescent probe.

Many pathological processes include nitric oxide (NO), a signaling transduction molecule. Tumors, cardiovascular, cerebrovascular, neurodegenerative, and other illnesses are linked to abnormal NO levels. Thus, evaluating NO levels in vitro and in vivo is crucial for studying chemical biology process of associated disorders. This work devised and manufactured a coumarin-based fluorescent probe ZPS-NO to detect nitric oxide (NO). The reaction between ZPS-NO and NO produced a highly selective and sensitive optical response that caused a powerful fluorescence "turn-on" effect with a ultra-low NO detection limit of 14.5 nM. Furthermore, the probe was applied to sense and image NO in living cells and inflammatory model of zebrafish, as well as to detect NO in periodontitis patients' saliva samples. We anticipate that probe ZPS-NO will serve as a practical and effective tool for assessing the interactions and evaluation of periodontitis development.

Ripretinib inhibits HIV-1 transcription through modulation of PI3K-AKT-mTOR.

Despite the effectiveness of antiretroviral therapy (ART) in prolonging the lifespan of individuals infected with HIV-1, it does not offer a cure for acquired immunodeficiency syndrome (AIDS). The "block and lock" approach aims to maintain the provirus in a state of extended transcriptional arrest. By employing the "block and lock" strategy, researchers endeavor to impede disease progression by preventing viral rebound for an extended duration following patient stops receiving ART. The crux of this strategy lies in the utilization of latency-promoting agents (LPAs) that are suitable for impeding HIV-1 provirus transcription. However, previously documented LPAs exhibited limited efficacy in primary cells or samples obtained from patients, underscoring the significance of identifying novel LPAs that yield substantial outcomes. In this study, we performed high-throughput screening of FDA-approved compound library in the J-Lat A2 cell line to discover more efficacious LPAs. We discovered ripretinib being an LPA candidate, which was validated and observed to hinder proviral activation in cell models harboring latent infections, as well as CD4+ T cells derived from infected patients. We demonstrated that ripretinib effectively impeded proviral activation through inhibition of the PI3K-AKT-mTOR signaling pathway in the HIV-1 latent cells, thereby suppressing the opening states of cellular chromatin. The results of this research offer a promising drug candidate for the implementation of the "block and lock" strategy in the pursuit of an HIV-1 cure.

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E-deficient mice.

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 µM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.