H3K18 lactylation accelerates liver fibrosis progression through facilitating SOX9 transcription.

Liver fibrosis is a significant health concern globally due to its association with severe liver conditions like cirrhosis and liver cancer. Histone lactylation has been implicated in the progression of hepatic fibrosis, but its specific role in liver fibrosis, particularly regarding H3K18 lactylation, remained unclear. To investigate this, we established in vivo and in vitro models of liver fibrosis using carbon tetrachloride (CCl4) injection in rats and stimulation of hepatic stellate cells (HSCs) with TGF-ß1, respectively. We found that histone lactylation, particularly H3K18 lactylation, was upregulated in both CCl4-induced rats and TGF-ß1-activated HSCs, indicating its potential involvement in liver fibrosis. Further experiments revealed that lactate dehydrogenase A (LDHA) knockdown inhibited H3K18 lactylation and had a beneficial effect on liver fibrosis by suppressing HSC proliferation, migration, and extracellular matrix (ECM) deposition. This suggests that H3K18 lactylation promotes liver fibrosis progression. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that H3K18 lactylation facilitated the transcription of SOX9, a transcription factor associated with fibrosis. Importantly, overexpression of SOX9 counteracted the effects of LDHA silencing on activated HSCs, indicating that SOX9 is downstream of H3K18 lactylation in promoting liver fibrosis. In summary, this study uncovers a novel mechanism by which H3K18 lactylation contributes to liver fibrosis by activating SOX9 transcription. This finding opens avenues for exploring new therapeutic strategies for hepatic fibrosis targeting histone lactylation pathways.

Fluorescent chemosensors facilitate the visualization of plant health and their living environment in sustainable agriculture.

Globally, 91% of plant production encounters diverse environmental stresses that adversely affect their growth, leading to severe yield losses of 50-60%. In this case, monitoring the connection between the environment and plant health can balance population demands with environmental protection and resource distribution. Fluorescent chemosensors have shown great progress in monitoring the health and environment of plants due to their high sensitivity and biocompatibility. However, to date, no comprehensive analysis and systematic summary of fluorescent chemosensors used in monitoring the correlation between plant health and their environment have been reported. Thus, herein, we summarize the current fluorescent chemosensors ranging from their design strategies to applications in monitoring plant-environment interaction processes. First, we highlight the types of fluorescent chemosensors with design strategies to resolve the bottlenecks encountered in monitoring the health and living environment of plants. In addition, the applications of fluorescent small-molecule, nano and supramolecular chemosensors in the visualization of the health and living environment of plants are discussed. Finally, the major challenges and perspectives in this field are presented. This work will provide guidance for the design of efficient fluorescent chemosensors to monitor plant health, and then promote sustainable agricultural development.

Dexmedetomidine inhibited arrhythmia susceptibility to adrenergic stress in RyR2R2474S mice through regulating the coupling of membrane potential and intracellular calcium.

BACKGROUND: Dexmedetomidine (DEX), a highly selective α2-adrenoceptor agonist, can decrease the incidence of arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the underlying mechanisms by which DEX affects cardiac electrophysiological function remain unclear. METHODS: Ryanodine receptor (RyR2) heterozygous R2474S mice were used as a model for CPVT. WT and RyR2R2474S/+ mice were treated with isoproterenol (ISO) and DEX, and electrocardiograms were continuously monitored during both in vivo and ex vivo experiments. Dual-dye optical mapping was used to explore the anti-arrhythmic mechanism of DEX. RESULTS: DEX significantly reduced the occurrence and duration of ISO-induced of VT/VF in RyR2R2474S/+ mice in vivo and ex vivo. DEX remarkably prolonged action potential duration (APD80) and calcium transient duration (CaTD80) in both RyR2R2474S/+ and WT hearts, whereas it reduced APD heterogeneity and CaT alternans in RyR2R2474S/+ hearts. DEX inhibited ectopy and reentry formation, and stabilized voltage-calcium latency. CONCLUSION: DEX exhibited an antiarrhythmic effect through stabilizing membrane voltage and intracellular Ca2+. DEX can be used as a beneficial perioperative anesthetic for patients with CPVT or other tachy-arrhythmias.

The clinical efficacy and safety of berberine in the treatment of non-alcoholic fatty liver disease: a meta-analysis and systematic review.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent worldwide, emerging as a significant health issue on a global scale. Berberine exhibits potential for treating NAFLD, but clinical evidence remains inconclusive. This meta-analysis was conducted to assess the efficacy and safety of berberine for treating NAFLD. METHODS: This study was registered with PROSPERO (No. CRD42023462338). Identification of randomized controlled trials (RCTs) involved searching 6 databases covering the period from their initiation to 9 September 2023. The primary outcomes comprised liver function markers such as glutamyl transpeptidase (GGT), alanine transaminase (ALT), aspartate transaminase (AST), lipid indices including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), homeostasis model assessment for insulin resistance (HOMA-IR) and body mass index (BMI). Review Manager 5.4 and STATA 17.0 were applied for analysis. RESULTS: Among 10 RCTs involving 811 patients, berberine demonstrated significant reductions in various parameters: ALT (standardized mean difference (SMD) = - 0.72), 95% confidence interval (Cl) [- 1.01, - 0.44], P < 0.00001), AST (SMD = - 0.79, 95% CI [- 1.17, - 0.40], P < 0.0001), GGT (SMD = - 0.62, 95% CI [- 0.95, - 0.29], P = 0.0002), TG (SMD = - 0.59, 95% CI [- 0.86, - 0.31], P < 0.0001), TC(SMD = - 0.74, 95% CI [- 1.00, - 0.49], P < 0.00001), LDL-C (SMD = - 0.53, 95% CI [- 0.88, - 0.18], P = 0.003), HDL-C (SMD = - 0.51, 95% CI [- 0.12, 1.15], P = 0.11), HOMA-IR (SMD = - 1.56, 95% CI [- 2.54, - 0.58], P = 0.002), and BMI (SMD = - 0.58, 95% CI [- 0.77, - 0.38], P < 0.00001). Importantly, Berberine exhibited a favorable safety profile, with only mild gastrointestinal adverse events reported. CONCLUSION: This meta-analysis demonstrates berberine's efficacy in improving liver enzymes, lipid profile, and insulin sensitivity in NAFLD patients. These results indicate that berberine shows promise as an adjunct therapy for NAFLD. Trial registration The protocol was registered with PROSPERO (No. CRD42023462338). Registered on September 27, 2023.

Pretreatment with an antibiotics cocktail enhances the protective effect of probiotics by regulating SCFA metabolism and Th1/Th2/Th17 cell immune responses.

BACKGROUND: Probiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis. RESULTS: The inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells. CONCLUSIONS: Abx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention.

Aquatic photosynthetic carbon pump driven by periodic temperature variations affects dissolved inorganic carbon and hydrochemical characteristics in a groundwater-fed reservoir.

Under the influence of periodic temperature variations, biogeochemical cycling in water bodies is markedly affected by the periodic thermal stratification processes in subtropical reservoirs or lakes. In current studies, there is insufficient research on the influence and mechanism of dissolved inorganic carbon (DIC) distribution in karst carbon-rich groundwater-fed reservoirs under the coupled effects of thermal structure stratification and the biological carbon pump (BCP) effect. To address this issue, the Dalongdong (DLD) reservoir in the subtropical region of southern China was chosen as the site for long-term monitoring and research on relevant physicochemical parameters of water, DIC, and its stable carbon isotope (δ13CDIC), CO2 emission flux, as well as the reservoir's thermal stratification index. The results show that: (1) the DLD reservoir is a typical warm monomictic reservoir, which exhibits regular variations of mixing period-stratification period-mixing period on a yearly scale due to thermal structure changes; (2) DIC was consumed by aquatic photosynthetic organisms in the epilimnion during the stratification period, leading to a decrease in DIC concentration, partial pressure of CO2 (pCO2) and CO2 emission flux, and an increase in stable carbon isotope (δ13CDIC). During the mixing period, the trend was reversed; (3) During the thermal stratification, aquatic photosynthesis and water temperature were the primary factors controlling DIC variations in both the epilimnion and thermocline. Regarding the hypolimnion, calcite dissolution, organic matter decomposition, and water temperature were the dominant controlling factors. These results indicate that although carbon-rich karst groundwater provides a plentiful supply of DIC in the DLD reservoir, its availability is still influenced by variations in the reservoir's thermal structure and the metabolic processes of aquatic photosynthetic organisms. Therefore, to better estimate the regional carbon budget in a reservoir or lake, future studies should especially consider the combined effects of BCP and thermal structure variations on carbon variations.

High-frequency dynamics of CO2 emission flux and its influencing factors in a subtropical karst groundwater-fed reservoir, south China.

Revealing the magnitude, dynamics, and influencing factors of CO2 emissions across the water-air interface in karst water with high frequency is crucial for accurately assessing the carbon budget in a karst environment. Due to the limitations of observation methods, the current research is still very insufficient. To solve the above problems and clarify the main influencing factors of CO2 emission in karst water, this study selected Dalongdong (DLD) Reservoir, located in the typical karst peak and valley area in southwest China, to carry out a multi-parameter high-frequency monitoring study from January to December 2021, and used the thin boundary model method to estimate the CO2 flux across the water-air interface (CF). The average annual flux of DLD reservoir is 84.48 mmol·(m2·h)-1, which represents a CO2 source overall. However, during the stratification period in August, there is a transient carbon sink due to negative CO2 emission. The alteration of thermal stratification in water is crucial in regulating the seasonal variation of CF. Meanwhile, the diurnal variation is significantly influenced by changes in hydrochemical parameters during the thermal stratification stage. Compared to low wind speeds (<3 m/s), high wind speeds (≥3 m/s) have a greater impact on the CO2 flux. Furthermore, high-frequency continuous data revealed that the reservoir triggered a CO2 pulse emission during the turnover process, primarily at night, leading to unusually high CO2 flux values. It is of great significance to monitor and reveal the process, flux, and control factors of CO2 flux in land water at a high-frequency strategy. They will help improve the accuracy of regional or watershed carbon budgets and clarify the role of global land water in the global carbon budget.

The Potential Mechanisms of Arrhythmia in Coronavirus disease-2019.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) leads to coronavirus disease-2019 (COVID-19) which can cause severe cardiovascular complications including myocardial injury, arrhythmias, acute coronary syndrome and others. Among these complications, arrhythmias are considered serious and life-threatening. Although arrhythmias have been associated with factors such as direct virus invasion leading to myocardial injury, myocarditis, immune response disorder, cytokine storms, myocardial ischemia/hypoxia, electrolyte abnormalities, intravascular volume imbalances, drug interactions, side effects of COVID-19 vaccines and autonomic nervous system dysfunction, the exact mechanisms of arrhythmic complications in patients with COVID-19 are complex and not well understood. In the present review, the literature was extensively searched to investigate the potential mechanisms of arrhythmias in patients with COVID-19. The aim of the current review is to provide clinicians with a comprehensive foundation for the prevention and treatment of arrhythmias associated with long COVID-19.

Application of metabolomics in oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent malignancy affecting the head and neck region. The prognosis for OSCC patients remains unfavorable due to the absence of precise and efficient early diagnostic techniques. Metabolomics offers a promising approach for identifying distinct metabolites, thereby facilitating early detection and treatment of OSCC. OBJECTIVE: This review aims to provide a comprehensive overview of recent advancements in metabolic marker identification for early OSCC diagnosis. Additionally, the clinical significance and potential applications of metabolic markers for the management of OSCC are discussed. RESULTS: This review summarizes metabolic changes during the occurrence and development of oral squamous cell carcinoma and reviews prospects for the clinical application of characteristic, differential metabolites in saliva, serum, and OSCC tissue. In this review, the application of metabolomic technology in OSCC research was summarized, and future research directions were proposed. CONCLUSION: Metabolomics, detection technology that is the closest to phenotype, can efficiently identify differential metabolites. Combined with statistical data analyses and artificial intelligence technology, it can rapidly screen characteristic biomarkers for early diagnosis, treatment, and prognosis evaluations.

Exploring the comorbidity mechanisms between psoriasis and obesity based on bioinformatics.

BACKGROUND: Psoriasis is a chronic, recurrent, immune-mediated inflammatory skin disease characterized by erythematous scaly lesions. Obesity is currently a major global health concern, increasing the risk of diseases such as cardiovascular diseases and diabetes. Since the correlation between psoriasis and obesity, as well as hypertension, diabetes, and cardiovascular diseases, has been clinically evidenced, it is of certain clinical significance to explore the mechanisms underlying the comorbidity of psoriasis with these conditions. MATERIALS AND METHODS: Gene targets for both diseases were obtained from the Gene Expression Omnibus (GEO) comprehensive gene expression database. Differential gene analysis, intersection gene analysis, construction and visualization of protein-protein interaction networks (PPI) using R software, Cytoscape 3.8.2 software, online tools such as String, and enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed, with relevant graphics generated. RESULTS: Analysis identified 29 intersecting genes between the two diseases, with 10 key targets such as S100A7 and SERPINB4. Enrichment analysis indicated their involvement in regulating biological processes such as leukocyte chemotaxis, migration, and chronic inflammatory responses through cellular structures such as intracellular vesicles and extracellular matrix. Molecular functions, including RAGE receptor binding, Toll-like receptor binding, and fatty acid binding, were found to simultaneously regulate psoriasis and obesity. CONCLUSION: Psoriasis and obesity may mutually influence each other through multiple targets and pathways, emphasizing the importance of considering comorbidity treatment and daily care in clinical practice.

Comparing perioperative outcomes between regional anesthesia and general anesthesia in patients undergoing hip fracture surgery: a systematic review and meta-analysis.

PURPOSE: Nearly all patients with hip fractures undergo surgical treatment. The use of different anesthesia techniques during surgery may influence the clinical outcomes. The optimal anesthetic technique for patients undergoing hip fracture surgery is still controversial. We performed this updated systematic review and meta-analysis to compare clinical outcomes of patients undergoing hip fracture surgery with different anesthesia techniques. SOURCE: Articles published from 2000 to May 2023 were included from MEDLINE, Embase, Web of Science, and the Cochrane Library. We included randomized controlled trials and observational studies comparing general anesthesia (GA) with regional anesthesia (RA) for the outcomes of 30-day mortality, 90-day mortality, in-hospital mortality, perioperative complications, length of hospital stay, and length of surgery in patients undergoing hip fracture surgery. Subgroup analyses were performed for the outcomes based on study design (randomized controlled trials or observational studies). We used a random-effects model for all analyses. PRINCIPAL FINDINGS: In this meta-analysis, we included 12 randomized controlled trials. There was no difference in postoperative 30-day mortality between the two groups (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.44 to 1.74; I2 = 0%). The incidence of intraoperative hypotension was lower in patients who received RA vs GA (OR, 0.52; 95% CI, 0.38 to 0.72; I2 = 0%). No significant differences were observed in 90-day mortality, in-hospital mortality, postoperative delirium, pneumonia, myocardial infarction, venous thromboembolism, length of surgery, and length of hospital stay. CONCLUSION: In this updated systematic review and meta-analysis, RA did not reduce postoperative 30-day mortality in hip fracture surgery patients compared to GA. Fewer patients receiving RA had intraoperative hypotension than those receiving GA did. Apart from intraoperative hypotension, the data showed no differences in complications between the two anesthetic techniques. STUDY REGISTRATION: PROSPERO (CRD42023411854); registered 7 April 2023.

RéSUMé: OBJECTIF: Presque toutes les personnes ayant subi une fracture de la hanche se font opérer. L'utilisation de différentes techniques d'anesthésie pendant la chirurgie peut influencer les issues cliniques. La technique d'anesthésie optimale pour la patientèle bénéficiant de chirurgie de fracture de la hanche est encore controversée. Nous avons réalisé cette mise à jour par revue systématique et méta-analyse pour comparer les issues cliniques des personnes bénéficiant d'une chirurgie de fracture de la hanche avec différentes techniques d'anesthésie. SOURCES: Les articles publiés de 2000 à mai 2023 ont été inclus à partir des bases de données MEDLINE, Embase, Web of Science et Cochrane Library. Nous avons inclus des études randomisées contrôlées et des études observationnelles comparant l'anesthésie générale (AG) à l'anesthésie régionale (AR) pour les issues de mortalité à 30 jours, de mortalité à 90 jours, de mortalité intrahospitalière, de complications périopératoires, de durée de séjour à l'hôpital et de durée de la chirurgie pour les personnes bénéficiant d'une chirurgie de fracture de la hanche. Des analyses de sous-groupes ont été réalisées pour les issues en fonction de la méthodologie utilisée (étude randomisée contrôlée ou étude observationnelle). Un modèle à effets aléatoires a été utilisé pour toutes les analyses. CONSTATATIONS PRINCIPALES: Dans cette méta-analyse, nous avons inclus 12 études randomisées contrôlées. Il n'y avait pas de différence dans la mortalité postopératoire à 30 jours entre les deux groupes (rapport de cotes [RC], 0,88; intervalle de confiance à 95 % [IC], 0,44 à 1,74; I2 = 0 %). L'incidence d'hypotension peropératoire était plus faible chez les patient·es ayant reçu une AR vs une AG (RC, 0,52; IC 95 %, 0,38 à 0,72; I2 = 0 %). Aucune différence significative n'a été observée dans les issues de mortalité à 90 jours, de mortalité intrahospitalière, de delirium postopératoire, de pneumonie, d'infarctus du myocarde, de thromboembolie veineuse, de durée de la chirurgie, et de durée du séjour à l'hôpital. CONCLUSION: Dans cette revue systématique avec méta-analyse, l'anesthésie régionale n'a pas réduit la mortalité postopératoire à 30 jours chez les personnes ayant bénéficié d'une chirurgie de fracture de la hanche par rapport à l'anesthésie générale. Une proportion moindre de patient·es ayant reçu une AR présentaient une hypotension peropératoire par rapport aux personnes ayant reçu une AG. En dehors de l'hypotension peropératoire, les données n'ont montré aucune différence dans les complications entre les deux techniques anesthésiques. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42023411854); enregistrée le 7 avril 2023.

Long-term music stimulating alleviated the inflammatory responses caused by acute noise stress on the immune organs of broilers by NF-κB signaling pathway.

As an environmental enrichment, music can positively influence the immune function, while noise has an adverse effect on the physical and mental health of humans and animals. However, whether music-enriched environments mitigate noise-induced acute stress remains unclear. To investigate the anti-inflammatory effects of music on the immune organs of broiler chickens under conditions of early-life acute noise stress, 140 one-day-old white feather broilers (AA) were randomly divided into four groups: control (C), the music stimulation (M) group, the acute noise stimulation (N) group, the acute noise stimulation followed by music (NM) group. At 14 days of age, the N and NM groups received 120 dB noise stimulation for 10 min for one week. After acute noise stimulation, the NM group and M group were subjected to continuous music stimulation for 14 days (6 h per day, 60 dB). At 28 days of age, the body temperature of the chicks, the histopathological changes, quantification of ROS-positive density and apoptosis positivity in tissues of spleen, thymus, and bursa of Fabricius (BF) were measured. The results showed that acute noise stimulation led to an increase in the number and area of splenic microsomes and the cortex/medulla ratio of the detected immune organs. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) of immune tissues of broilers in N group were decreased compared to the broilers in C group, while the mRNA levels of malondialdehyde (MDA), TNF-α, IL-1, and IL-1ß increased. In addition, the gene and protein expression levels of IKK, NF-κB, and IFN-γ of three immune organs from broilers in the N group were increased. Compared to the C and N group, chickens from the NM group showed a decrease in the number and area of splenic follicles, an increase in the activities of SOD and GSH-Px, and a decrease in the expression levels of MDA, TNF-α, IL-1, and IL-1ß. Therefore, a music-enriched environment can attenuate oxidative stress induced by acute noise stimulation, inhibiting the activation of the NF-κB signaling pathway and consequently alleviating the inflammatory response in immune organs.

Investigation of lambda-cyhalothrin resistance in Spodoptera frugiperda: Heritability, cross-resistance, and mechanisms.

Lambda-cyhalothrin, a representative pyrethroid insecticide widely used for Spodoptera frugiperda control in China, poses challenges due to the development of resistance. This study investigates the realized heritability, inheritance pattern, cross-resistance, and resistance mechanisms to lambda-cyhalothrin. After 21 generations of selection, the lambda-cyhalothrin-resistant strain (G21) developed a 171.11-fold resistance compared to a relatively susceptible strain (RS-G9), with a realized heritability (h2) of 0.11. Cross-resistance assays revealed that lambda-cyhalothrin-resistant strains showed no significant cross-resistance to the majority of tested insecticides. Genetic analysis indicated that lambda-cyhalothrin resistance in S. frugiperda was autosomal, incompletely dominant, and polygenic inheritance. The P450 enzyme inhibitor PBO significantly enhanced lambda-cyhalothrin toxicity in the resistant strains. Compared with the RS-G9 strain, the P450 enzyme activity was significantly increased and multiple P450 genes were significantly up-regulated in the lambda-cyhalothrin-resistant strains. RNAi targeting the most overexpressed P450 genes (CYP337B5 and CYP321B1) significantly increased the susceptibility of resistant S. frugiperda larvae to lambda-cyhalothrin. This study provides comprehensive insights into lambda-cyhalothrin resistance in S. frugiperda, and the results are helpful for developing effective resistance management strategies of this pest.

LncRNA SNHG12 regulated by WTAP aggravated the oxygen-glucose deprivation/reperfusion-induced injury in bEnd.3 cell.

OBJECTIVES: Previous studies have identified abnormal expression of lncRNA SNHG12 in ischemic stroke, but the underlying molecular mechanism remains unclear. MATERIALS AND METHODS: Through database predictions, m6A methylation sites were found on SNHG12, suggesting post-transcriptional modification. To further elucidate the role of SNHG12 and m6A methyltransferase WTAP in oxygen-glucose deprivation/reperfusion (OGD/R)-induced damage in cerebral microvascular endothelial cells, we conducted investigations. Additionally, we examined the impact of m6A methyltransferase WTAP on SNHG12 expression. RESULTS: Overexpressing SNHG12 in bEnd.3 cells was found to inhibit cell proliferation and promote apoptosis, as well as activate the production of reactive oxygen species and inflammatory cytokines (E-selectin, IL-6 and MCP-1), along with angiogenic proteins (VEGFA and FGFb). Conversely, SNHG12 knockdown alleviated OGD/R-induced damage to BEnd.3 cells, resulting in improved cell proliferation, reduced apoptosis, decreased ROS and LDH production, as well as diminished expression of inflammatory cytokines (E-selectin, IL-6 and MCP-1) and angiogenic proteins (VEGFA and FGFb). Furthermore, WTAP was found to positively regulate SNHG12 expression, and WTAP knockdown in bEnd.3 cells under the OGD/R conditions inhibited cell proliferation, promoted apoptosis, and increased ROS and LDH production. CONCLUSION: These findings suggest that WTAP may play a crucial role in SNHG12-mediated OGD/R-induced damage in bEnd.3 cells. More molecular experiments are needed to further analyze its mechanism. Overall, our study helps to enrich our understanding of the dysregulation of SNHG12 in ischemic stroke.

Anthropogenic Activities Generate High-Refractory Black Carbon along the Yangtze River Continuum.

Combustion-driven particulate black carbon (PBC) is a crucial slow-cycling pool in the organic carbon flux from rivers to oceans. Since the refractoriness of PBC stems from the association of non-homologous char and soot, the composition and source of char and soot must be considered when investigating riverine PBC. Samples along the Yangtze River continuum during different hydrological periods were collected in this study to investigate the association and asynchronous combustion drive of char and soot in PBC. The results revealed that PBC in the Yangtze River, with higher refractory nature, accounts for 13.73 ± 6.89% of particulate organic carbon, and soot occupies 37.53 ± 11.00% of PBC. The preponderant contribution of fossil fuel combustion to soot (92.57 ± 3.20%) compared to char (27.55 ± 5.92%), suggested that fossil fuel combustion is a crucial driver for PBC with high soot percentage. Redundancy analysis and structural equation modeling confirmed that the fossil fuel energy used by anthropogenic activities promoting soot is the crucial reason for high-refractory PBC. We estimated that the Yangtze River transported 0.15-0.23 Tg of soot and 0.15-0.25 Tg of char to the ocean annually, and the export of large higher refractory PBC to the ocean can form a long-term sink and prolong the residence time of terrigenous carbon.

Bioinspired PROTAC-induced macrophage fate determination alleviates atherosclerosis.

Atherosclerosis is a major cause of death and disability in cardiovascular disease. Atherosclerosis associated with lipid accumulation and chronic inflammation leads to plaques formation in arterial walls and luminal stenosis in carotid arteries. Current approaches such as surgery or treatment with statins encounter big challenges in curing atherosclerosis plaque. The infiltration of proinflammatory M1 macrophages plays an essential role in the occurrence and development of atherosclerosis plaque. A recent study shows that TRIM24, an E3 ubiquitin ligase of a Trim family protein, acts as a valve to inhibit the polarization of anti-inflammatory M2 macrophages, and elimination of TRIM24 opens an avenue to achieve the M2 polarization. Proteolysis-targeting chimera (PROTAC) technology has emerged as a novel tool for the selective degradation of targeting proteins. But the low bioavailability and cell specificity of PROTAC reagents hinder their applications in treating atherosclerosis plaque. In this study we constructed a type of bioinspired PROTAC by coating the PROTAC degrader (dTRIM24)-loaded PLGA nanoparticles with M2 macrophage membrane (MELT) for atherosclerosis treatment. MELT was characterized by morphology, size, and stability. MELT displayed enhanced specificity to M1 macrophages as well as acidic-responsive release of dTRIM24. After intravenous administration, MELT showed significantly improved accumulation in atherosclerotic plaque of high fat and high cholesterol diet-fed atherosclerotic (ApoE-/-) mice through binding to M1 macrophages and inducing effective and precise TRIM24 degradation, thus resulting in the polarization of M2 macrophages, which led to great reduction of plaque formation. These results suggest that MELT can be considered a potential therapeutic agent for targeting atherosclerotic plaque and alleviating atherosclerosis progression, providing an effective strategy for targeted atherosclerosis therapy.

The RXFP2-PLC/PKC signaling pathway mediates INSL3-induced regulation of the proliferation, migration and apoptosis of mouse gubernacular cells.

BACKGROUND: Testicular hypoplasia can affect the sexual and reproductive ability in adulthood, and even increase the risk of cancer. Abnormal development of the gubernaculum is one of the important factors of testicular hypoplasia. Therefore, a study of the structure and function of the gubernaculum is an important but neglected new breakthrough point for investigating the normal/abnormal development of the testis. Previous findings showed that Insulin like factor 3 (INSL3) is a key factor regulating the growth of gubernaculum, however, the mechanism by which INSL3 acts on the gubernaculum remains unknown. Therefore, we probed the mechanism associated with INSL3-induced the proliferation, migration, and apoptosis of gubernacular cells in mice. METHODS: A culture cell model of neonatal mice gubernaculum is established by INSL3 intervention. We blocked PLC/PKC signaling pathway with U73122 pretreat to investigate the role of the PLC/PKC signaling pathway. The changes of cell proliferation, migration, and apoptosis were detected by molecular biological methods. In addition, the levels of PCNA and F-action were detected by immunofluorescence and western blotting. RESULTS: We found that INSL3 can promote the proliferation and migration of gubernacular cells and inhibit their apoptosis, meanwhile, INSL3 significantly up-regulated PLC/PKC protein phosphorylation. However, treatment with the PLC/PKC signaling pathway inhibitor U73122 significantly inhibited these effects of INSL3. Besides, we found that INSL3 could up-regulate the protein expression level of PCNA and F-actin, while the PCNA and F-actin expression was significantly weakened after U73122 pretreatment. CONCLUSIONS: This research revealed that INSL3 binding to RXFP2 may up-regulate the expression levels of PCNA and F-actin by activating the PLC/PKC signaling pathway to promote the proliferation and migration of gubernacular cells. It suggests that the RXFP2-PLC/PKC axis may serve as a novel molecular mechanism by which INSL3 regulates growth of the gubernaculum.

Electroacupuncture promotes neurogenesis in the dentate gyrus and improves pattern separation in an early Alzheimer's disease mouse model.

BACKGROUND: Impaired pattern separation occurs in the early stage of Alzheimer's disease (AD), and hippocampal dentate gyrus (DG) neurogenesis participates in pattern separation. Here, we investigated whether spatial memory discrimination impairment can be improved by promoting the hippocampal DG granule cell neogenesis-mediated pattern separation in the early stage of AD by electroacupuncture (EA). METHODS: Five familial AD mutations (5 × FAD) mice received EA treatment at Baihui and Shenting points for 4 weeks. During EA, mice were intraperitoneally injected with BrdU (50 mg/kg) twice a day. rAAV containing Wnt5a shRNA was injected into the bilateral DG region, and the viral efficiency was evaluated by detecting Wnt5a mRNA levels. Cognitive behavior tests were conducted to assess the impact of EA treatment on cognitive function. The hippocampal DG area Aß deposition level was detected by immunohistochemistry after the intervention; The number of BrdU+/CaR+ cells and the gene expression level of calretinin (CaR) and prospero homeobox 1(Prox1) in the DG area of the hippocampus was detected to assess neurogenesis by immunofluorescence and western blotting after the intervention; The gene expression levels of FZD2, Wnt5a, DVL2, p-DVL2, CaMKII, and p-CaMKII in the Wnt signaling pathway were detected by Western blotting after the intervention. RESULTS: Cognitive behavioral tests showed that 5 × FAD mice had impaired pattern separation (P < 0.001), which could be improved by EA (P < 0.01). Immunofluorescence and Western blot showed that the expression of Wnt5a in the hippocampus was decreased (P < 0.001), and the neurogenesis in the DG was impaired (P < 0.001) in 5 × FAD mice. EA could increase the expression level of Wnt5a (P < 0.05) and promote the neurogenesis of immature granule cells (P < 0.05) and the development of neuronal dendritic spines (P < 0.05). Interference of Wnt5a expression aggravated the damage of neurogenesis (P < 0.05), weakened the memory discrimination ability (P < 0.05), and inhibited the beneficial effect of EA (P < 0.05) in AD mice. The expression level of Wnt pathway related proteins such as FZD2, DVL2, p-DVL2, CAMKII, p-CAMKII increased after EA, but the effect of EA was inhibited after Wnt5a was knocked down. In addition, EA could reduce the deposition of Aß plaques in the DG without any impact on Wnt5a. CONCLUSION: EA can promote hippocampal DG immature granule cell neogenesis-mediated pattern separation to improve spatial memory discrimination impairment by regulating Wnt5a in 5 × FAD mice.

Relationship between BMI and risk of impaired glucose tolerance and impaired fasting glucose in Chinese adults: a prospective study.

BACKGROUND: Current studies in most Western countries have largely focused on body mass index (BMI) as an important risk factor for impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), which have different pathophysiological bases. In people with obesity, the prevalence of IGT is higher and the prevalence of IFG is lower. The prevalence of IGT in the Asian population is higher than that in the white population, and the obesity rate in China is still increasing. However, few cohort studies explore the relationship between BMI and the incidence of IGT and IFG in China. We aimed to explore the relationship between BMI and the risk of IGT and IFG in Chinese adults and analyze the differences between them. METHODS: The baseline data were obtained from the 2010 China Chronic Disease and Risk Factor Surveillance, of which 20 surveillance sites were followed up from 2016 to 2017. Finally, in this study, a total of 5,578 studies were grouped into BMI categories of underweight (BMI < 18.5 kg/m2), normal weight (18.5-23.9 kg/m2), overweight (24.0-27.9 kg/m2), and obesity (≥ 28.0 kg/m2). We used the unconditional logistic regression model to analyze the relationship between BMI and the risk of IGT and IFG. RESULTS: During an average follow-up of 6.4 years, 562 developed IGT and 257 developed IFG. After age, gender, urban and rural areas, physical activity, family history of diabetes, hypertension, abdominal obesity, dyslipidemia, and other factors were adjusted, overweight increased the risk of IGT by 35% [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.08-1.70], and obesity increased the risk of IGT by 77% (OR 1.77, 95% CI 1.27-1.47). After the factors consistent with the above were adjusted, only obesity increased the risk of IFG by 122% (OR 2.22, 95% CI 1.39-3.54). CONCLUSIONS: In China, obesity is an important risk factor for IGT and IFG, and the risk of IGT increases during the overweight stage.

Childhood granulomatous periorificial dermatitis in 31 Chinese children successfully treated with oral roxithromycin.

Data regarding the treatment of childhood granulomatous periorificial dermatitis (CGPD) using oral therapies are limited. This study included 31 Chinese children with CGPD treated with oral roxithromycin. After 12 weeks of treatment, 90.3% of the patients recovered, and there were no severe adverse effects. Our results suggest that oral roxithromycin is an effective and safe treatment for CGPD.