Luteolin Alleviates Diabetic Nephropathy Fibrosis Involving AMPK/NLRP3/TGF-ß Pathway.

Purpose: Luteolin is a promising candidate for diabetic nephropathy due to its potential anti-inflammatory and anti-fibrotic properties. This study explored the molecular mechanisms through which luteolin combats fibrosis in DN. Methods: Potential targets affected by luteolin and genes associated with DN were collected from databases. Overlapping targets between luteolin and diabetic nephropathy were identified through Venn analysis. A protein-protein interaction network was constructed using these common targets, and critical pathways and targets were elucidated through GO and KEGG analysis. These pathways and targets were confirmed using a streptozotocin-induced mouse model. Luteolin was administered at 45 mg/kg and 90 mg/kg. Various parameters were evaluated, including body weight, blood glucose levels, and histopathological examinations. Protein levels related to energy metabolism, inflammation, and fibrosis were quantified. Results: Fifty-three targets associated with luteolin and 36 genes related to diabetic nephropathy were extracted. The AGE-RAGE signaling pathway was the key pathway impacted by luteolin in diabetic nephropathy. Key molecular targets include TGF-ß, IL-1ß, and PPARG. Luteolin reduced body weight and blood glucose levels, lowered the left kidney index, and improved insulin and glucose tolerance. Furthermore, luteolin mitigated inflammatory cell infiltration, basement membrane thickening, and collagen deposition in the kidney. Luteolin up-regulated the protein expression of p-AMPKα (Th172) while simultaneously down-regulated the protein expression of p-NF-ĸB (p65), NLRP3, TGF-ß1, α-SMA, and Collagen I. Conclusion: Luteolin mitigated renal fibrosis by alleviating energy metabolism disruptions and inflammation by modulating the AMPK/NLRP3/TGF-ß signaling pathway.

STOP1 regulates CCX1-mediated Ca2+ homeostasis for plant adaptation to Ca2+ deprivation.

Calcium (Ca) is essential for plant growth and stress adaptation, yet its availability is often limited in acidic soils, posing a major threat to crop production. Understanding the intricate mechanisms orchestrating plant adaptation to Ca deficiency remains elusive. Here, we show that the Ca deficiency-enhanced nuclear accumulation of the transcription factor SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) in Arabidopsis thaliana confers tolerance to Ca deprivation, with the global transcriptional responses triggered by Ca deprivation largely impaired in the stop1 mutant. Notably, STOP1 activates the Ca deprivation-induced expression of CATION/Ca2+ EXCHANGER 1 (CCX1) by directly binding to its promoter region, which facilitates Ca2+ efflux from endoplasmic reticulum to cytosol to maintain Ca homeostasis. Consequently, the constitutive expression of CCX1 in the stop1 mutant partially rescues the Ca deficiency phenotype by increasing Ca content in the shoots. These findings uncover the pivotal role of the STOP1-CCX1 axis in plant adaptation to low Ca, offering alternative manipulating strategies to improve plant Ca nutrition in acidic soils and extending our understanding of the multifaceted role of STOP1.

Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor.

The intrinsic tenase complex (iXase) is an attractive antithrombotic target to treat or prevent pathological thrombosis with negligible bleeding risk. Fucosylated glycosaminoglycan (FG) is a promising anticoagulant by inhibiting iXase. A depolymerized FG (dHG-5) as an anticoagulant has been approved for clinical trials. Given that dHG-5 is a multi-component drug candidate consisting of a homologous series of oligosaccharides, it is difficult to predict a clear pharmacokinetics. Here, as a major oligosaccharide component, the tetradecasaccharide (oHG-14) was purified from dHG-5 and its structure was defined as L-Fuc3S4S-α(1,3)-L-Δ4,5GlcA-α(1,3)-{D-GalNAc4S6S-ß(1,4)-[L-Fuc3S4S-α(1,]3)-D-GlcA-ß(1,3)-}3-D-GalNAc4S6S-ß(1,4)-[L-Fuc3S4S-α(1,]3)-D-GlcA-ol. oHG-14 showed potent iXase inhibitory activity in vitro and antithrombotic effect in vivo comparable to dHG-5. After single subcutaneous administration of oHG-14 at 8, 14.4 and 32.4 mg/kg to rats, the absolute bioavailability was 71.6 %-80.9 % determined by the validated bioanalytical methods. The maximum concentration (Cmax) was 3.73, 8.07, and 11.95 µg/mL, respectively, and the time reaching Cmax (Tmax) was about 1 h. oHG-14 was mainly excreted by kidney as the parent compound with the elimination kinetics of first-order linear model. Anticoagulant activity of oHG-14 was positively correlated with its concentration in rat plasma. The pharmacokinetics/pharmacodynamics (PK/PD) of oHG-14 is similar to that of dHG-5. This study could provide supportive data for the clinical trial of dHG-5 and further development of pure oligosaccharide as an antithrombotic drug candidate.

Exploring the Mechanism of Isoforskolin against Asthma Based on Network Pharmacology and Experimental Verification.

In this study, network pharmacology combined with biological experimental verification was utilized to screen the targets of isoforskolin (ISOF) and investigate the potential underlying mechanism of ISOF against asthma. Asthma-related targets were screened from the Genecards and DisGeNET databases. SEA and Super-PRED databases were used to obtain the targets of ISOF. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were employed to identify enriched regulatory pathways of key targets in ISOF acting on asthma. Then, a protein-protein interaction (PPI) network was constructed via STRING database and hub genes of ISOF against asthma were further screened using molecular docking. Finally, CCK-8, qPCR, and Western blotting were performed to confirm the targets of ISOF in treating asthma. A total of 96 drug potential therapeutic targets from the relevant databases were screened out. KEGG pathway enrichment analysis predicted that the target genes might be involved in the PI3K-Akt pathway. The core targets of ISOF in treating asthma were identified by the PPI network and molecular docking, including MAPK1, mTOR, and NFKB1. Consistently, in vitro experiments showed that ISOF acting on asthma was involved in inflammatory response by reducing the expression of MAPK1, mTOR, and NFKB1. The present study reveals that MAPK1, mTOR, and NFKB1 might be key targets of ISOF in asthma treatment and the anti-asthma effect might be related to the PI3K-AKT signaling pathway.

Identification and experimental validation of PYCARD as a crucial PANoptosis-related gene for immune response and inflammation in COPD.

Chronic inflammatory and immune responses play key roles in the development and progression of chronic obstructive pulmonary disease (COPD). PANoptosis, as a unique inflammatory cell death modality, is involved in the pathogenesis of many inflammatory diseases. We aim to identify critical PANoptosis-related biomarkers and explore their potential effects on respiratory tract diseases and immune infiltration landscapes in COPD. Total microarray data consisting of peripheral blood and lung tissue datasets associated with COPD were obtained from the GEO database. PANoptosis-associated genes in COPD were identified by intersecting differentially expressed genes (DEGs) with genes involved in pyroptosis, apoptosis, and necroptosis after normalizing and removing the batch effect. Furthermore, GO, KEGG, PPI network, WGCNA, LASSO-COX, and ROC curves analysis were conducted to screen and verify hub genes, and the correlation between PYCARD and infiltrated immune cells was analyzed. The effect of PYCARD on respiratory tract diseases and the potential small-molecule agents for the treatment of COPD were identified. PYCARD expression was verified in the lung tissue of CS/LPS-induced COPD mice. PYCARD was a critical PANoptosis-related gene in all COPD patients. PYCARD was positively related to NOD-like receptor signaling pathway and promoted immune cell infiltration. Moreover, PYCARD was significantly activated in COPD mice mainly by targeting PANoptosis. PANoptosis-related gene PYCARD is a potential biomarker for COPD diagnosis and treatment.

Synergistic Enhancement of Isoforskolin and Dexamethasone Against Sepsis and Acute Lung Injury Mouse Models.

Background: Sepsis is initiated by the dysfunctional response of the host immune system to infection. Septic shock and acute lung injury (ALI) are the main etiology of death caused by sepsis. Glucocorticoids, which are commonly used in clinic to antagonize the inflammatory response of sepsis, may cause serious side effects. Isoforskolin (ISOF) from the plant Coleus forskohlii stimulates adenylyl cyclase, increases the cAMP level and inhibits inflammatory response. The aim of this study was to investigate the synergistic effect of ISOF with dexamethasone (DEX) to prevent and ameliorate septic inflammation. Methods: Lipopolysaccharide (LPS) of 30 and 5 mg/kg (iv.) was used to induce sepsis and ALI mice model respectively in vivo. BEAS-2B cells stimulated by LPS were applied as cell model in vitro. The cumulative survival of mice with LPS-induced sepsis and the histopathological changes of lungs in mice with acute lung injury were observed, and the secretion of pro-inflammatory cytokines was analyzed by ELISA. The expression of RGS2 in BEAS-2B cells was detected by immunoblotting assay and PCR. Results: In the sepsis mice model, ISOF (10 mg/kg) combined with DEX (10 mg/kg.) (ip.) pretreatment significantly increased mice survival rate from 33.3% to 58.3%, which was significantly higher than that of ISOF or DEX treated alone. In the ALI mice model, ISOF, DEX pretreatment alone and combined application attenuated pulmonary pathological changes in ALI mice. Furthermore, ISOF, DEX alone or combined administration decreased MPO, MDA, IL-6, and IL-8 levels, while significantly synergistic effects were observed in the combined treatment group compared with ISOF or DEX alone. In BEAS-2B cells, combined pretreatment with ISOF and DEX significantly decreased the expression of IL-8 and increased the expression of RGS2. Conclusion: The results indicated that ISOF in combination with DEX synergistically improves survival rate and attenuates ALI in mice model through anti-inflammatory and antioxidant effects.

[Responses of tree growth and intrinsic water-use efficiency of Robinia pseudoacacia to climate factors]. / åˆºæ§ç”Ÿé•¿å’Œå† åœ¨æ°´åˆ†åˆ©ç”¨æ•ˆçŽ‡å¯¹æ°”å€™å› å­çš„å“åº”.

We investigated tree growth in Robinia pseudoacacia plantations at Ansai in Shaanxi Province and at Ji-xian in Shanxi Province by comparing the tree-ring width, basal area increase (BAI), δ13C value, intrinsic water-use efficiency (iWUE), and stomatal regulation. We quantified the responses of tree growth and iWUE to climatic factors at each site. The tree-ring width at Ansai and Jixian decreased with stand age, whereas the BAI at Ansai increased, and that at Jixian decreased after the BAI peaked. The δ13C value and iWUE of trees at Jixian were higher than those at Ansai. The iWUE of trees at both sites was similar to the constant intercellular CO2 concentration/atmospheric CO2 concentration (Ci/Ca) scenario, indicating that the Ci of trees was elevated with increasing Ca, while the stomata remained open. The BAI at Ansai was significantly positively correlated with highest temperature in May, relative humidity in June, precipitation in August, relative humidity in September, and standardized precipitation evapotranspiration index (SPEI) in September and October of current year, but negatively correlated with temperature in June. The BAI at Jixian was significantly positively correlated with SPEI in June and July, and lowest temperature in October of current year. The iWUE of trees at Ansai was significantly positively correlated with relative humidity and precipitation in June of the current year, but negatively correlated with minimum temperature in May, relative humidity in June, and temperature and maximum temperature in July of current year. A significant positive correlation between iWUE of trees at Jixian and lowest temperature in June of current year was detected. At the annual scale, the BAI of trees at Ansai was positively correlated with precipitation and SPEI, but no significant relationship was observed for trees at Jixian. However, the iWUE of trees at both sites was significantly affected by precipitation. Path analysis showed that SPEI and minimum temperature had a direct effect on BAI and iWUE of trees at Ansai, whereas precipitation and average temperature indirectly affected BAI and iWUE through SPEI. The highest temperature had a direct effect on tree growth at Jixian, whereas precipitation, minimum temperature, and average temperature had direct effects on iWUE. These results suggested that SPEI was the main climatic factor that affected the growth of R. pseudoacacia, while Ci was an important physiological factor. Our results could provide reference for the protection and management of R. pseudoacacia plantations under climate change.

Novel results on asymptotic stability and synchronization of fractional-order memristive neural networks with time delays: The 0<뫲1 case.

This paper investigates the asymptotic stability and synchronization of fractional-order (FO) memristive neural networks with time delays. Based on the FO comparison principle and inverse Laplace transform method, the novel sufficient conditions for the asymptotic stability of a FO nonlinear system are given. Then, based on the above conclusions, the sufficient conditions for the asymptotic stability and synchronization of FO memristive neural networks with time delays are investigated. The results in this paper have a wider coverage of situations and are more practical than the previous related results. Finally, the validity of the results is checked by two examples.

Coinfection with influenza virus and non-typeable Haemophilus influenzae aggregates inflammatory lung injury and alters gut microbiota in COPD mice.

Background: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with high mortality rates. Viral and bacterial coinfection is the primary cause of AECOPD. How coinfection with these microbes influences host inflammatory response and the gut microbiota composition is not entirely understood. Methods: We developed a mouse model of AECOPD by cigarette smoke exposure and sequential infection with influenza H1N1 virus and non-typeable Haemophilus influenzae (NTHi). Viral and bacterial titer was determined using MDCK cells and chocolate agar plates, respectively. The levels of cytokines, adhesion molecules, and inflammatory cells in the lungs were measured using Bio-Plex and flow cytometry assays. Gut microbiota was analyzed using 16S rRNA gene sequencing. Correlations between cytokines and gut microbiota were determined using Spearman's rank correlation coefficient test. Results: Coinfection with H1N1 and NTHi resulted in more severe lung injury, higher mortality, declined lung function in COPD mice. H1N1 enhanced NTHi growth in the lungs, but NTHi had no effect on H1N1. In addition, coinfection increased the levels of cytokines and adhesion molecules, as well as immune cells including total and M1 macrophages, neutrophils, monocytes, NK cells, and CD4 + T cells. In contrast, alveolar macrophages were depleted. Furthermore, coinfection caused a decline in the diversity of gut bacteria. Muribaculaceae, Lactobacillus, Akkermansia, Lachnospiraceae, and Rikenella were further found to be negatively correlated with cytokine levels, whereas Bacteroides was positively correlated. Conclusion: Coinfection with H1N1 and NTHi causes a deterioration in COPD mice due to increased lung inflammation, which is correlated with dysbiosis of the gut microbiota.

Gastrodin and Gastrodigenin Improve Energy Metabolism Disorders and Mitochondrial Dysfunction to Antagonize Vascular Dementia.

Vascular dementia (VD) is the second most common dementia syndrome worldwide, and effective treatments are lacking. Gastrodia elata Blume (GEB) has been used in traditional Chinese herbal medicine for centuries to treat cognitive impairment, ischemic stroke, epilepsy, and dizziness. Gastrodin (p-hydroxymethylphenyl-b-D-glucopyranoside, Gas) and Gastrodigenin (p-hydroxybenzyl alcohol, HBA) are the main bioactive components of GEB. This study explored the effects of Gas and HBA on cognitive dysfunction in VD and their possible molecular mechanisms. The VD model was established by bilateral common carotid artery ligation (2-vessel occlusion, 2-VO) combined with an intraperitoneal injection of sodium nitroprusside solution. One week after modeling, Gas (25 and 50 mg/kg, i.g.) and HBA (25 and 50 mg/kg, i.g.) were administered orally for four weeks, and the efficacy was evaluated. A Morris water maze test and passive avoidance test were used to observe their cognitive function, and H&E staining and Nissl staining were used to observe the neuronal morphological changes; the expressions of Aß1-42 and p-tau396 were detected by immunohistochemistry, and the changes in energy metabolism in the brain tissue of VD rats were analyzed by targeted quantitative metabolomics. Finally, a Hippocampus XF analyzer measured mitochondrial respiration in H2O2-treated HT-22 cells. Our study showed that Gas and HBA attenuated learning memory dysfunction and neuronal damage and reduced the accumulation of Aß1-42, P-Tau396, and P-Tau217 proteins in the brain tissue. Furthermore, Gas and HBA improved energy metabolism disorders in rats, involving metabolic pathways such as glycolysis, tricarboxylic acid cycle, and the pentose phosphate pathway, and reducing oxidative damage-induced cellular mitochondrial dysfunction. The above results indicated that Gas and HBA may exert neuroprotective effects on VD by regulating energy metabolism and mitochondrial function.

Oligosaccharide Blocks PAR1 (Proteinase-Activated Receptor 1)-PAR4-Mediated Platelet Activation by Binding to Thrombin Exosite II and Impairs Thrombosis.

BACKGROUND: Inappropriate activation and aggregation of platelets can lead to arterial thrombosis. Thrombin is the most potent platelet agonist that activates human platelets via two PARs (proteinase-activated receptors), PAR1 and PAR4. The aim is to study the activity and mechanism of an oligosaccharide HS-11 (the undecasaccharide, derived from sea cucumber Holothuria fuscopunctata) in inhibiting thrombin-mediated platelet activation and aggregation and to evaluate its antithrombotic activity. METHODS: Platelet activation was analyzed by detecting CD62P/P-selectin expression using flow cytometry. The HS-11-thrombin interaction and the binding site were studied by biolayer interferometry. Intracellular Ca2+ mobilization of platelets was measured by FLIPR Tetra System using Fluo-4 AM (Fluo-4 acetoxymethyl). Platelet aggregation, thrombus formation, and bleeding Assay were assessed. RESULTS: An oligosaccharide HS-11, depolymerized from fucosylated glycosaminoglycan from sea cucumber Holothuria fuscopunctata blocks the interaction of thrombin with PAR1 and PAR4 complex by directly binding to thrombin exosite II, and completely inhibits platelet signal transduction, including intracellular Ca2+ mobilization and protein phosphorylation. Furthermore, HS-11 potently inhibits thrombin-PARs-mediated platelet aggregation and reduces thrombus formation in a model of ex vivo thrombosis. CONCLUSIONS: The study firstly report that the fucosylated glycosaminoglycan oligosaccharide has antiplatelet activity by binding to thrombin exosite II, and demonstrates that thrombin exosite II plays an important role in the simultaneous activation of PAR1 and PAR4, which may be a potential antithrombotic target for effective treatment of arterial thrombosis.

The role of lung macrophages in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) as a common, preventable and treatable chronic respiratory disease in clinic, gets continuous deterioration and we can't take effective intervention at present. Lung macrophages (LMs) are closely related to the occurrence and development of COPD, but the specific mechanism is not completely clear. In this review we will focus on the role of LMs and potential avenues for therapeutic targeting for LMs in COPD.

Influence of Exposure Period and Angle Alteration on the Flexural Resilience and Mechanical Attributes of Photosensitive Resin.

Despite the large number of studies addressing the effect of acrylic resin polymerization concerning flexural properties, limited research has been conducted on the manufacturing impact on a polymer's mechanical properties. Photosensitive resinous materials are used in various engineering applications where they may be exposed to multiple detrimental environments during their lifetime. Therefore, there is a need to understand the impact of an environment on the service life of resins. Thus, flexural tests were conducted to study the effects of exposure time and angle on the flexural strength of resins. Herein, the main objective was to explore the strength, stability, and flexural durability of photosensitive resin (EPIC-2000ST) fabricated at different exposure times (E) and angle deviation varying from 0° to 85° with a 5° increment. The samples in circular rings were manufactured and divided into five groups according to their exposure time (E): 10 s, 20 s, 30 s, 40 s, and 50 s. In each exposure time, we designed rings via SolidWorks software and experimentally fabricated at different oblique angles (OA) varying from 0° to 85° with a 5° increment during each fabrication, i.e., OA = 0°, 5°, 10°, 15°, 20°, 25°, 30°, 35°, 40°, 45°, 50°, 55°, 60°, 65°, 70°, 75°, 80°, and 85°. Flexural strength was evaluated using a three-point bending test. Optical electron microscopy was used to examines the samples' exterior, interior, and ruptured surfaces. Our experimental analysis shows that flexural strength was significantly enhanced by increasing exposure time and at higher oblique angles. However, at lower angles and less exposure time, mechanical flexural resilience declines.

Geographic pattern of phytoplankton community and their drivers in lakes of middle and lower reaches of Yangtze River floodplain, China.

Disentangling the relative contributions of deterministic and stochastic processes was critical to compressive understanding of underlying mechanism governing geographic pattern and assembly of phytoplankton community, while it was seldom performed in connected lakes under human pressure. Here, we investigated phytoplankton community pattern in relation to environmental and spatial factors over 81 lakes located in the middle and lower reaches of Yangtze River (MLYR) floodplain, where many lakes suffered from eutrophication and cyanobacterial blooms. A majority of MLYR lakes had higher phytoplankton abundance surpassing 107 cells/L and were dominated by common bloom-forming cyanobacterial genera, including Pseudanabaena, Microcystis, Merismopedia, Dolichospermum, Limnothrix, and Raphidiopsis. Phytoplankton community exhibited a striking geographical pattern both for taxonomic and functional compositions, while functional groups were less sensitive, and dissimilarity in communities displayed no significant increases with increasing geographical distance. Further, species richness explained much higher percentage of community variations than species turnover, indicating a reduced effect of environmental filtering of phytoplankton species with tolerance to similar environments in connected MLYR lakes. Both deterministic and stochastic processes governed assembly and biogeographic of phytoplankton community. Variation partition analysis showed that spatial factors exhibited greater influence on phytoplankton community compared to environmental variables. The stronger influence of spatial factors was further demonstrated by Mantel test and neutral community model. These findings indicate that deterministic and stochastic processes exhibited similar biogeographic patterns for phytoplankton community in MLYR lakes, but stochastic process was overwhelmingly dominated. Moreover, a large proportion of unexplained variation implies that complex interactions exist to shape assembly mechanism of phytoplankton community in MLYR lakes.

Unearthing the alleviatory mechanisms of hydrogen sulfide in aluminum toxicity in rice.

Hydrogen sulfide (H2S) improves aluminum (Al) resistance in rice, however, the underlying mechanism remains unclear. In the present study, treatment with 30-µM Al significantly inhibited rice root growth and increased the total Al content, apoplastic and cytoplasm Al concentration in the rice roots. However, pretreatment with NaHS (H2S donor) reversed these negative effects. Pretreatment with NaHS significantly increased energy production under Al toxicity conditions, such as by increasing the content of ATP and nonstructural carbohydrates. In addition, NaHS stimulated the AsA-GSH cycle to decrease the peroxidation damage induced by Al toxicity. Pretreatment with NaHS significantly inhibited ethylene emissions in the rice and then inhibited pectin synthesis and increased the pectin methylation degree to reduce cell wall Al deposition. The phytohormones indole-3-acetic and brassinolide were also involved in the alleviation of Al toxicity by H2S. The transcriptome results further confirmed that H2S alleviates Al toxicity by increasing the pathways relating to material and energy metabolism, redox reactions, cell wall components, and signal transduction. These findings improve our understanding of how H2S affects rice responses to Al toxicity, which will facilitate further studies on crop safety.

A multifunctional green antibacterial rapid hemostasis composite wound dressing for wound healing.

Rapid hemostasis and antibacterial properties are essential for novel wound dressings to promote wound healing. In particular, timely and rapid hemostasis could be of benefit to reduce the mortality caused by excessive bleeding loss. Herein, we present a novel strategy of combining electrospinning technology with post-modification technology to prepare a multifunctional wound dressing, cellulose diacetate-based composite wound dressing (CDCE), with rapid hemostasis and antibacterial activity. It is interesting that the CDCE wound dressing had superhydrophilicity, high water absorption, and strong absorbing capacity, which could eliminate the exudate around the wound in a timely manner and further promote rapid hemostasis. Additionally, its excellent antibacterial properties could inhibit severe infection in the wound and accelerate wound healing. Based on these advantages, the novel CDCE wound dressing could promote wound contraction and further accelerate wound healing compared with the common traditional wound dressing gauze. Taken together, the multifunctional CDCE wound dressing has high potential for clinical application in the future.

Isoforskolin, an adenylyl cyclase activator, attenuates cigarette smoke-induced COPD in rats.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by limited airflow due to pulmonary and alveolar abnormalities from exposure to cigarette smoke (CS). Current therapeutic drugs are limited and the development of novel treatments to prevent disease progression is challenging. Isoforskolin (ISOF) from the plant Coleus forskohlii is an effective activator of adenylyl cyclase (AC) isoforms. Previously we found ISOF could attenuate acute lung injury in animal models, while the effect of ISOF on COPD has not been elucidated. PURPOSE: In this study, we aimed to evaluate the efficacy of ISOF on COPD and reveal its potential mechanisms. METHODS: A rat model of COPD was established by long-term exposure to CS, then the rats were orally administered with ISOF (0.5, 1 and 2 mg/kg). The pulmonary function, lung morphology, inflammatory cells and cytokines in serum or bronchoalveolar lavage fluid (BALF) were evaluated. Transcriptomics, proteomics and network pharmacology analysis were utilized to identify potential mechanisms of ISOF. Droplet digital PCR was used to detect the mRNA expression of AC1-10 in donor lung tissues. AC activation was determined in recombinant human embryonic kidney 293 (HEK293) cells stably expressing human AC isoforms. In addition, ISOF caused trachea relaxation ex vivo were assessed in isolated trachea rings from guinea pigs. RESULTS: ISOF significantly ameliorated pathological damage of lung tissue and improved pulmonary function in COPD rats. ISOF treatment decreased the number of inflammatory cells in peripheral blood, and also the levels of pro-inflammatory cytokines in serum and BALF. Consistent with omics-based analyses, ISOF markedly downregulated the mTOR level in lung tissue. Flow cytometry analysis revealed that ISOF treatment reduced the ratio of Th17/Treg cells in peripheral blood. Furthermore, the expression levels of AC1 and AC2 are relatively higher than other AC isoforms in normal lung tissues, and ISOF could potently activate AC1 and AC2 in vitro and significantly relax isolated guinea pig trachea. CONCLUSION: Collectively, our studies suggest that ISOF exerts its anti-COPD effect by improving lung function, anti-inflammation and trachea relaxation, which may be related to AC activation, mTOR signaling and Th17/Treg balance.

Isoforskolin Alleviates AECOPD by Improving Pulmonary Function and Attenuating Inflammation Which Involves Downregulation of Th17/IL-17A and NF-κB/NLRP3.

Chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide, is widely considered to be related to cigarette smoke (CS), and viral infections trigger acute exacerbation of COPD (AECOPD). Isoforskolin (ISOF) is a bioactive component from the plant Coleus forskohlii, native to Yunnan in China. It has been demonstrated that ISOF has anti-inflammatory effect on acute lung injury animal models. In the present study, we investigated the efficacy and mechanism of ISOF for the prevention and treatment of AECOPD. Mice were exposed to CS for 18 weeks and then infected with influenza virus A/Puerto Rico/8/34 (H1N1). ISOF (0.5, 2 mg/kg) was intragastrically administered once a day after 8 weeks of exposure to cigarette smoke when the body weight and lung function of model mice declined significantly. The viral load, pulmonary function, lung morphology, Th17 cells, and inflammatory cytokines in lung tissues were evaluated. The expression of nuclear factor κB (NF-κB) and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome pathways were detected. The results showed that ISOF treatment reduced the viral load in the lung homogenate, decreased the lung index of model mice, and lung pathological injuries were alleviated. ISOF also improved the pulmonary function with increased FEV0.1/FVC and decreased Rn and Rrs. The levels of inflammatory mediators (TNF-α, IL-1ß, IL-6, IL-17A, MCP-1, MIG, IP-10, and CRP) in the lung homogenate were reduced after ISOF treatment. ISOF decreased the proportion of Th17 cells in the lung tissues by the flow cytometry test, and the protein expression levels of RORγt and p-STAT3 were also decreased. Furthermore, ISOF significantly inhibited the activation of NF-κB signaling and NLRP3 inflammasome in the lung tissues of model mice. In conclusion, ISOF alleviates AECOPD by improving pulmonary function and attenuating inflammation via the downregulation of proinflammatory cytokines, Th17/IL-17 A, and NF-κB/NLRP3 pathways.

[Research advance in the roles of water-nitrogen-oxygen factors in mediating rice growth, photosynthesis and nitrogen utilization in paddy soils.] / ç¨»ç”°æ°´æ°®æ°§çŽ¯å¢ƒå› å­å¯¹æ°´ç¨»ç”Ÿé•¿å‘è‚²ã€å ‰åˆä½œç”¨å’Œæ°®åˆ©ç”¨çš„è°ƒæŽ§ç ”ç©¶è¿›å±•.

Water and nitrogen are two important factors controlling rice growth and development. Suitable water-nitrogen interaction can alter nitrogen forms and oxygen environmental factors via regulating water content in the rhizosphere of paddy soil, promote the construction of root morphology, improve leaf photosynthesis and the allocation equilibrium of the photosynthetic products between the source and sink organs, and consequently increase rice population quality and grain yield. The microbial regulation mechanisms driven by the environmental factors (e.g. water, nitrogen and oxygen) also play an important role in improving nitrogen utilization efficiency in rice-soil system. Here, we reviewed the research progress in water-nitrogen interaction, and briefly discussed the effects of water, nitrogen form, and dissolved oxygen on rice growth, photosynthesis, carbon and nitrogen metabolism, nitrogen conversion and the underlying microbiological mechanism. We proposed several key directions for future researches: 1) to quantitatively investigate the spatial and temporal variations of dissolved oxygen in rhizosphere and their dominant environmental drivers under different water and nitrogen regimes; 2) to evaluate the responses of root-sourced signal to rhizosphere dissolved oxygen in different rice genotypes, and uncover its intrinsic mechanisms involved in rice growth and development; 3) to investigate the effects of key microbial process driven by the rhizosphere oxygen environment on the soil nitrogen conversion and rice nitrogen utilization.

Donepezil down-regulates propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation in the brain of bilateral common carotid artery occlusion-induced vascular dementia rats.

Vascular dementia (VaD), caused by stroke or small vessel disease, is the second-most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris water maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Aß1-42 in BCCAO rats by enzyme-linked immunosorbent assay. Post-translational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlights the importance of PTMs in neurodegenerative diseases. In this study, we used western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl-PTMs.