Long-term exposure to third-hand smoke could accelerate biological aging via mitochondrial dysfunction: Evidence from population and animal studies.

The relationship between third-hand smoke (THS) exposure and lifespan remains inadequately explored. Our study sought to clarify the effects of THS on aging and lifespan. In this pursuit, our cross-sectional analysis assessed hematological aging markers in 986 non-smokers and examined lifespan alterations using a Drosophila model. THS exposure levels were quantified through survey metrics consistent with the Global Adult Tobacco Survey. The findings revealed that THS exposure significantly accelerated biological aging, with exposed individuals exhibiting an average increase in biological age of 3.04 years compared to their unexposed counterparts (p < 0.05). Correspondingly, the Drosophila model reflected these outcomes, showing a reduction in lifespan by 16.07 days (p < 0.01). Proteomic analyses identified MRPL2 as a pivotal protein in THS-induced aging, linking its expression to mitochondrial dysfunction and oxidative stress. Further metabolomic profiling highlighted disruptions in energy metabolism pathways. Follow-up in vitro experiments confirmed the role of MRPL2 in the aging processes at the cellular level. Overall, our results indicate that THS exposure is a significant accelerant of aging, providing new perspectives on the health consequences of environmental smoke residues.

Massive Electro-Microfluidic Particle Assembly Patterns in Droplet Array for Information Encoding.

The assembly of colloidal particles into micro-patterns is essential in optics, informatics, and microelectronics. However, it is still a challenge to achieve quick, reversible, and precise assembly patterns within micro-scale spaces like droplets. Hereby, a method is presented that utilizes in-plane dielectrophoresis to precisely manipulate particle assemblies within microscale droplets. The electro-microfluidic particle assembly platform, equipped with ingenious electrode designs, enables the formation of diverse micro-patterns within a droplet array. The tunability, similarity, stability, and reversibility of this platform are demonstrated. The ability to assemble letters, numbers, and Morse code patterns within the droplet array underscores its potential for information encoding. Furthermore, using an example with four addressing electrodes beneath a droplet, 16 distinct pieces of information through electrical stimuli is successfully encoded. This unique capability facilitates the construction of a dynamic electronic token, indicating promising applications in anti-counterfeiting technologies.

Therapeutic effects of Lianhua Qingke on COPD and influenza virus-induced exacerbation of COPD are associated with the inhibition of NF-κB signaling and NLRP3 inflammasome responses.

Lianhua Qingke (LHQK), a traditional Chinese medicine (TCM) used clinically for the treatment of respiratory diseases with acute tracheobronchitis, and cough, has demonstrated promising efficacy in suppressing inflammation, inhibitingmucin secretion, reducing goblet cell hyperplasia andmaintainingairway epithelial integrity. However, its efficacy in managing chronic obstructive pulmonary disease (COPD) progression, particularly virus-induced acute exacerbations of COPD (AECOPD),remains unclear. Here, cigarette smoke (CS)-induced COPD and CS+virus (influenza H1N1)-triggered AECOPD mouse models were employed to evaluated the therapeutic potential of LHQK. The findings demonstrated that LHQK treatment led to significant improved pulmonary function, suppressed pulmonary inflammation, alleviated lung histopathological changes, and preserved airway epithelial integrity in COPD mice. Additionally, LHQK treatment effectively inhibited viral replication in the lungs of AECOPD mice and decreased recruitment of immune cells (M1 macrophages, progenitor-exhausted T cells and CD8 + T cells) to the lungs. Western blot analysis indicated that the therapeutic effects of LHQK are associated with the inhibition ofNF-κB signaling and NLRP3 inflammasome activation. Collectively, these findings elucidate the underlying mechanisms by which LHQK mitigates COPD and AECOPD, thereby supporting its potential as a therapeutic option for individuals afflicted with these conditions.

Elevation of p53 sensitizes obese kidney to adriamycin-induced aberrant lipid homeostasis via repressing HNF4α-mediated FGF21 sensitivity.

INTRODUCTION: Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders appear progressively more severe after ADR-based chemotherapy in the obese state, and the specific molecular mechanism needs to be further clarified. OBJECTIVES: This study was designed to examine the role of p53-fibroblast growth factor 21 (FGF21) axis in ADR-induced renal injury aggravated by high-fat diet (HFD). METHODS: We engineered Fgf21 KO mice and used long-term (4 months) and short-term (0.5 months) HFD feeding, and ADR-injected mice, as well as STZ-induced type 1 diabetic mice and type 2 (db/db) diabetic mice to produce an in vivo model of nephrotoxicity. The specific effects of p53/FGF21 on the regulation of lipid metabolism disorders and its downstream mediators in kidney were subsequently elucidated using a combination of functional and pathological analysis, RNA-sequencing, molecular biology, and in vitro approaches. RESULTS: Long-term HFD feeding mice exhibited compromised effects of FGF21 on alleviation of renal dysfunction and lipid accumulation following ADR administration. However, these impairments were reversed by p53 inhibitor (pifithrin-α, PFT-α). PFT-α sensitized FGF21 actions in kidney tissues, while knockout of Fgf21 impaired the protective effects of PFT-α on lipid metabolism. Mechanistically, p53 impaired the renal expression of FGF receptor-1 (FGFR1) and thereby developed gradually into FGF21 resistance via inhibiting hepatocyte nuclear factor 4 alpha (HNF4α)-mediated transcriptional activation of Fgfr1. More importantly, exogenous supplementation of FGF21 or PFT-α could not only alleviate ADR-induced lipid metabolism disorder aggravated by HFD, but also reduce lipid accumulation caused by diabetic nephropathy. CONCLUSION: Given the difficulties in developing the long-acting recombinant FGF21 analogs for therapeutic applications, sensitizing obesity-impaired FGF21 actions by suppression of p53 might be a therapeutic strategy for maintaining renal metabolic homeostasis during chemotherapy.

Aberrant activation of p53-TRIB3 axis contributes to diabetic myocardial insulin resistance and sulforaphane protection.

INTRODUCTION: Insulin resistance (IR) is associated with multiple pathological features. Although p53- or TRIB3-orchestrated IR is extensively studied in adipose tissue and liver, the role of p53-TRIB3 axis in myocardial IR remains unknown, and more importantly target-directed therapies of myocardial IR are missing. OBJECTIVES: Considering the beneficial effects of sulforaphane (SFN) on cardiovascular health, it is of particular interest to explore whether SFN protects against myocardial IR with a focus on the regulatory role of p53-TRIB3 axis. METHODS: Mouse models including cardiac specific p53-overexpressing transgenic (p53-cTg) mice and Trib3 knockout (Trib3-KO) mice, combined with primary cardiomyocytes treated with p53 activator (nutlin-3a) and inhibitor (pifithrin-α, PFT-α), or transfected with p53-shRNA and Trib3-shRNA, followed by multiple molecular biological methodologies, were used to investigate the role of p53-TRIB3 axis in SFN actions on myocardial IR. RESULTS: Here, we report that knockdown of p53 rescued cardiac insulin-stimulated AKT phosphorylation, while up-regulation of p53 by nutlin-3a or p53-cTg mice blunted insulin sensitivity in cardiomyocytes under diabetic conditions. Diabetic attenuation of AKT-mediated cardiac insulin signaling was markedly reversed by SFN in p53-Tgfl/fl mice, but not in p53-cTg mice. Importantly, we identified TRIB3 was elevated in p53-cTg diabetic mice, and confirmed the physical interaction between p53 and TRIB3. Trib3-KO diabetic mice displayed improved insulin sensitivity in the heart. More specifically, the AMPKα-triggered CHOP phosphorylation and degradation were essential for p53 on the transcriptional regulation of Trib3. CONCLUSION: Overall, these results indicate that inhibiting the p53-TRIB3 pathway by SFN plays an unsuspected key role in the improvement of myocardial IR, which may be a promising strategy for attenuating diabetic cardiomyopathy (DCM) in diabetic patients.

Effect of Haoqin Qingdan Tang on influenza A virus through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway.

OBJECTIVE: Influenza, a viral respiratory illness, leads to seasonal epidemics and occasional pandemics. Given the rising resistance and adverse reactions associated with anti-influenza drugs, Traditional Chinese Medicine (TCM) emerges as a promising approach to counteract the influenza virus. Specifically, Haoqin Qingdan Tang (HQQDT), a TCM formula, has been employed as an adjuvant treatment for influenza in China. However, the active compounds and underlying mechanisms of HQQDT remain unknown. AIM: The aim of this study was to investigate HQQDT's antiviral and anti-inflammatory activities in both in vivo and in vitro, and further reveal its active ingredients and mechanism. METHODS: In vivo and in vitro experiments were conducted to verify the antiviral and anti-inflammatory activities of HQQDT. Subsequently, the active ingredients and mechanism of HQQDT were explored through combining high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS) analysis and network pharmacology. Finally, the examinations of cell cytokines and signaling pathways aimed to elucidate the predicted mechanisms. RESULTS: The results indicated that HQQDT exhibited inhibitory effects on influenza viruses A/PR/8/34 (H1N1), A/HK/1/68 (H3N2), and A/California/4/2009 (H1N1) in vitro. Furthermore, HQQDT enhanced the survival rate of influenza-infected mice, reduced the lung index and lung virus titer, and mitigated lung tissue damage in vivo. The proinflammatory cytokine expression levels upon influenza virus infection in PR8-induced A549 cells or mice were suppressed by HQQDT, including IL-6, IL-1ß, CCL2, CCL4, IP-10, interferon ß1 (IFN-ß1), the interferon regulatory factor 3 (IRF3), and hemagglutinin (HA). Twenty-two active components of HQQDT against influenza were identified using HPLC-Q-TOF-MS analysis. Based on network pharmacological predictions, the JAK/STAT signaling pathway is considered the most relevant for HQQDT's action against influenza. Finally, western blot assays revealed that HQQDT regulated the protein level of the JAK/STAT signaling pathway in PR8-infected A549 cells and lung tissue. CONCLUSION: These findings verified the antiviral and anti-inflammatory effects of HQQDT through JAK-STAT signaling pathway in influenza infections, laying the foundation for its further development.

Sangbaipi decoction exerted in vitro and in vivo anti-influenza effect through inhibiting viral proteins.

HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Sangbaipi Decoction (SBPD) is an effective treatment for lung diseases caused by phlegm-heat obstruction according to Jingyue Quanshu, and soothes panting by purging the lung meridian. It is composed of anti-pyretic herbs (e.g., Scutellaria baicalensis Georgi and Coptis chinensis Franch.) and antitussive herbs (e.g., Cortex Mori and Armeniacae Semen Amarum). Therefore, we hypothesized that SBPD has therapeutic effects on lung injury caused by influenza virus. AIM OF THE STUDY: This study aimed to explore anti-influenza activity, active components, and mechanisms of SBPD. MATERIALS AND METHODS: The anti-influenza activities of SBPD were determined in 48 h drug-treated MDCK cell model using CPE and plaque reduction assays, and 24 h drug-treated A549 cells using qRT-PCR. The in vivo efficacy of SBPD (1.0 g/kg/day and 0.5 g/kg/day) was evaluated in PR8 infected BALB/c mice. The chemical component was assessed through HPLC-Q-TOF MS/MS analysis. Network pharmacology was built via TCMSP, GeneCards, DisgeNet, OMIM, DrugBank databases, and Cytoscape software. Additionally, TOA, HI and NAI assays were employed to investigate impact on the virus replication cycle with different concentrations of SBPD (2.5 mg/mL, 1.25 mg/mL, or 0.625 mg/mL). RESULTS: In MDCK infected with viruses A/PR/8/34, A/Hong Kong/1/68, or A/California/4/2009, the IC50 values of SBPD were 0.80 mg/mL, 1.20 mg/mL, and 1.25 mg/mL. In A549 cells, SBPD treatment reduced cytokine expression (e.g., TNF-α, IL-6, IL-1ß) (p < 0.05). In PR8 infected BALB/c mice, SBPD improved the survival rate of infected mice, reduced lung index (p < 0.05), protected lung tissue from pathological damage, and regulated cytokine overexpression (p < 0.05). 29 components of SBPD were identified in SBPD treated mouse serum including some phytochemicals targeting influenza proteins. HI and NAI assays suggested the potential antiviral mechanism of SBPD through inhibition of HA and NA. CONCLUSION: This study is the first to demonstrate the anti-influenza and the anti-inflammatory effects of SBPD in vitro and in vivo. Its major anti-influenza phytochemicals were explored and its inhibitory effects on HA and NA protein were proved. It provides more options for anti-influenza drug discovery.

SESN2-Mediated AKT/GSK-3ß/NRF2 Activation to Ameliorate Adriamycin Cardiotoxicity in High-Fat Diet-Induced Obese Mice.

Aims: Obese patients are highly sensitive to adriamycin (ADR)-induced cardiotoxicity. However, the potential mechanism of superimposed toxicity remains to be elucidated. Sestrin 2 (SESN2), a potential antioxidant, could attenuate stress-induced cardiomyopathy; therefore, this study aims to explore whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high-fat diet (HFD)-induced obese mice. Results: The results revealed that obesity decreased SESN2 expression in ADR-exposed heart. And, HFD mice may predispose to ADR-induced cardiotoxicity, which was probably associated with inhibiting protein kinase B (AKT), glycogen synthase kinase-3 beta (GSK-3ß) phosphorylation and subsequently blocking nuclear localization of nuclear factor erythroid-2 related factor 2 (NRF2), ultimately resulting in cardiac oxidative damage. However, these destructive cascades and cardiac oxidative damage effects induced by HFD/sodium palmitate combined with ADR were blocked by overexpression of SESN2. Moreover, the antioxidant effect of SESN2 could be largely abolished by sh-Nrf2 or wortmannin. And sulforaphane, an NRF2 agonist, could remarkably reverse cardiac pathological and functional abnormalities caused by ADR in obese mice. Innovation and Conclusion: This study demonstrated that SESN2 might be a promising therapeutic target for improving anthracycline-related cardiotoxicity in obesity by upregulating activity of NRF2 via AKT/GSK-3ß/Src family tyrosine kinase signaling pathway. Antioxid. Redox Signal. 40, 598-615.

Integration of dietary nutrition and TRIB3 action into diabetes mellitus.

Despite intensive studies for decades, the common mechanistic correlations among the underlying pathology of diabetes mellitus (DM), its complications, and effective clinical treatments remain poorly characterized. High-quality diets and nutrition therapy have played an indispensable role in the management of DM. More importantly, tribbles homolog 3 (TRIB3), a nutrient-sensing and glucose-responsive regulator, might be an important stress-regulatory switch, linking glucose homeostasis and insulin resistance. Therefore, this review aimed to introduce the latest research progress on the crosstalk between dietary nutrition intervention and TRIB3 in the development and treatment of DM. This study also summarized the possible mechanisms involved in the signaling pathways of TRIB3 action in DM, in order to gain an in-depth understanding of dietary nutrition intervention and TRIB3 in the pathogenesis of DM at the organism level.

Anti-influenza virus activities and mechanism of antrafenine analogs.

Antrafenine is a drug initially designed for anti-inflammation uses. In this work we have synthesized a library of its structural analogs and tested the anti-influenza activities. These analogs belong to a group of 2-(quinolin-4-yl)amino benzamides or 2-(quinolin-4-yl)amino benzoate derivatives. Best performers were identified, namely 12, 34, 41, with IC50 against A/WSN/33 (H1N1) of 5.53, 3.21 and 6.73 µM respectively. These chemicals were also effective against A/PR/8/34 (H1N1), A/HK/1/68 (H3N2) and B/Florida/04/2006 viruses. Time-of-addition study and minigenome luciferase reporter assay both supported that the compounds act on the ribonucleoprotein (RNP) components. Using 34 and 41 as representative compounds, we determined by microscale thermophoresis that this group of compounds bind to both PA C-terminal domain and the nucleoprotein (NP) which is the most abundant subunit of the RNP. Taken together, we have identified a new class of anti-influenza compounds with dual molecular targets and good potential to be further developed. IMPORTANCE: The influenza viruses, especially influenza A and B subtypes, cause many deaths each year. The high mutation rate of the virus renders available therapeutics less effective with time. In this work we identify a new class of compounds, structurally similar to the anti-inflammation drug antrafenine, with good potency against influenza A strains. The IC50 of the best performers are within low micromolar range and thus have good potential for further development.

Network pharmacology associated anti-influenza mechanism research of Qingjie-Tuire Granule via STAT1/3 signaling pathway.

Qingjie-Tuire (QT) granule was approved for clinical use and its combination was reported to treat influenza infection. To explore its active component and mechanism, the components of QT granule were retrieved from UPLC-UC-Q-TOF/MS analysis. The genes corresponding to the targets were retrieved using GeneCards and TTD database. The herb-compound-target network was constructed by Cytoscape. The target protein-protein interaction network was built using STRING database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of QT granule to IAV were performed for further study. The regulation to different signaling transduction events and cytokine/chemokine expression of QT granule was evaluated using Western blotting and real-time qPCR. Totally, 47 compounds were identified and effect of QT granule on cell STAT1/3 signaling pathways was confirmed by A549 cell model. The efficiency of QT granule on host cell contributes to its clinical application and mechanism research.

Inverse correlations between serum carotenoids and respiratory morbidity and mortality: the Third National Health and Nutrition Examination Survey.

The objective was to evaluate the association between serum carotenoid levels and respiratory morbidity and mortality in a nationally representative sample of US adults. We assessed the association of serum carotenoid levels with respiratory morbidity and mortality using logistic regression and proportional hazards regression models. Meanwhile, a series of confounders were controlled in regression models and restricted cubic spline, which included age, sex, race, marriage, education, income, drinking, smoking, regular exercise, BMI, daily energy intake, vitamin E, vitamin C, fruit intake, vegetable intake, diabetes, hypertension, asthma, emphysema and chronic bronchitis. Compared with participants in the lowest tertiles, participants in the highest tertiles of serum total carotenoids, ß-cryptoxanthin and lutein/zeaxanthin levels had a significantly lower prevalence of emphysema (ORtotal carotenoids = 0·61, 95% CI: 0·41-0·89, ORß-cryptoxanthin = 0·67, 95% CI: 0·49-0·92), chronic bronchitis (ORß-cryptoxanthin = 0·66, 95% CI: 0·50-0·87) and asthma (Q2: ORlutein/zeaxanthin = 0·78, 95% CI: 0·62-0·97); participants in the highest tertiles of total carotenoids, α-carotene, lutein/zeaxanthin and lycopene had a lower risk of respiratory mortality (hazard ratio (HR)total carotenoids = 0·62, 95% CI: 0·42-0·90, HRα-carotene = 0·54, 95% CI: 0·36-0·82, HRlutein/zeaxanthin = 0·48, 95% CI: 0·33-0·71, HRlycopene = 0·66, 95% CI: 0·45-0·96) than those in the lowest tertiles. Higher serum total carotenoids and ß-cryptoxanthin levels is associated with decreased prevalence of emphysema and chronic bronchitis, and higher serum total carotenoids, α-carotene, lutein/zeaxanthin and lycopene levels had a lower mortality of respiratory disease.

Anti-influenza properties of tiliroside isolated from Hibiscus mutabilis L.

ETHNOPHARMACOLOGICAL RELEVANCE: Fu Rong Ye (FRY), the leaf of Hibiscus mutabilis L., is a Chinese medicinal herb used to treat coughs and respiratory diseases. FRY is the major herbal component of the patent medicine Fupo Ganmao Granules for treating common cold. However, its anti-influenza active components and mechanism were not identified. AIM: Here, we aim to a) isolate the anti-influenza phytochemicals from FRY extract and b) explore its anti-flu mechanism. MATERIAL AND METHODS: Bioassay guided isolation was performed to get anti-influenza virus components. Influenza virus infected cells and mouse model were employed for efficacy evaluation. RESULTS: Using bioassay-guided isolation, the flavonoid tiliroside was obtained, which inhibited four IAV strains in MDCK cells with EC50 ranging from 3.87 to 27.61 µM by suppressing the viral ribonucleoprotein activity. Tiliroside also significantly downregulated the expression of cytokines/chemokines in A549 cells, and protected 50% of PR8-infected BALB/c mice from death and at 800 mg/kg/day, improved lung edema conditions. CONCLUSION: Tiliroside is effective for influenza virus infection treatment and promising for further drug development. This study is the first to demonstrate that tiliroside in FRY acts against influenza virus.

Resveratrol and FGF1 Synergistically Ameliorates Doxorubicin-Induced Cardiotoxicity via Activation of SIRT1-NRF2 Pathway.

Doxorubicin (DOX) has received attention due to dose-dependent cardiotoxicity through abnormal redox cycling. Native fibroblast growth factor 1 (FGF1) is known for its anti-oxidative benefits in cardiovascular diseases, but possesses a potential tumorigenic risk. Coincidentally, the anti-proliferative properties of resveratrol (RES) have attracted attention as alternatives or auxiliary therapy when combined with other chemotherapeutic drugs. Therefore, the purpose of this study is to explore the therapeutic potential and underlying mechanisms of co-treatment of RES and FGF1 in a DOX-treated model. Here, various cancer cells were applied to determine whether RES could antagonize the oncogenesis effect of FGF1. In addition, C57BL/6J mice and H9c2 cells were used to testify the therapeutic potential of a co-treatment of RES and FGF1 against DOX-induced cardiotoxicity. We found RES could reduce the growth-promoting activity of FGF1. Additionally, the co-treatment of RES and FGF1 exhibits a more powerful cardio-antioxidative capacity in a DOX-treated model. The inhibition of SIRT1/NRF2 abolished RES in combination with FGF1 on cardioprotective action. Further mechanism analysis demonstrated that SIRT1 and NRF2 might form a positive feedback loop to perform the protective effect on DOX-induced cardiotoxicity. These favorable anti-oxidative activities and reduced proliferative properties of the co-treatment of RES and FGF1 provided a promising therapy for anthracycline cardiotoxicity during chemotherapy.

Urolithin M5 from the Leaves of Canarium album (Lour.) DC. Inhibits Influenza Virus by Targeting Neuraminidase.

Ganlanye (GLY), the leaf of Canarium album (Lour.) DC., is a traditional Chinese medicinal herb for warm disease treatment. We found that its aqueous extract could inhibit the influenza A virus. To find and characterize anti-influenza virus phytochemicals from GLY, we performed (1) bioassay-guided isolation, (2) a cell and animal assay, and (3) a mechanism study. Bioassay-guided isolation was used to identify the effective components. Influenza virus-infected MDCK cell and BALB/c mouse models were employed to evaluate the anti-influenza virus activities. A MUNANA assay was performed to find the NA inhibitory effect. As a result, urolithin M5 was obtained from the crude extract of GLY. It inhibited influenza virus activities in vitro and in vivo by suppressing the viral NA activity. In the MDCK cell model, urolithin M5 could inhibit an oseltamivir-resistant strain. In a PR8-infected mouse model, 200 mg/kg/d urolithin M5 protected 50% of mice from death and improved lung edema conditions. GLY was recorded as a major traditional herb for warm disease treatment. Our study identified GLY as a potent anti-influenza herb and showed urolithin M5 as the active component. We first report the in vivo activity of urolithin M5 and support the anti-influenza application of GLY.

Co-Treatment With Resveratrol and FGF1 Protects Against Acute Liver Toxicity After Doxorubicin Treatment via the AMPK/NRF2 Pathway.

Doxorubicin (DOX), an anthracycline type of chemotherapy, is an effective therapy for several types of cancer, but serious side effects, such as severe hepatotoxicity, limit its use currently. Accordingly, an effective therapeutic strategy to prevent DOX-related hepatotoxicity is urgently needed. Through the inhibition of oxidative stress, fibroblast growth factor 1 (FGF1) is an effect therapy for a variety of liver diseases, but its use is limited by an increased risk of tumorigenesis due to hyperproliferation. Resveratrol (RES), a natural product, inhibits the growth of many cancer cell lines, including liver, breast, and prostate cancer cells. Therefore, this study explored whether and how RES in combination with FGF1 can alleviate DOX-induced hepatotoxicity. The results showed that RES or FGF1 alone improved DOX-induced hepatic inflammation, apoptosis and oxidative stress, and these adverse effects were further attenuated after treatment with both RES and FGF1. Mechanistically, both in vivo and in vitro results showed that RES/FGF1 reduced oxidative stress and thereby alleviated liver injury by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and subsequently upregulating expression of antioxidant proteins in an adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. Together, our results not only demonstrate that co-treatment with RES and FGF1 significantly inhibited DOX-induced hepatic inflammation and apoptosis, but also that co-treatment with RES and FGF1 markedly suppressed DOX-induced hepatic oxidative stress, via targeting the AMPK/NRF2 pathway and subsequently ameliorating hepatic dysfunction. Thus, the combination of RES and FGF1 may provide a new therapeutic strategy for limiting DOX-induced hepatotoxicity.

Resveratrol Attenuates High Glucose-Induced Osteoblast Dysfunction via AKT/GSK3ß/FYN-Mediated NRF2 Activation.

Osteoblast dysfunction, induced by high glucose (HG), negatively impacts bone homeostasis and contributes to the pathology of diabetic osteoporosis (DOP). One of the most widely recognized mechanisms for osteoblast dysfunction is oxidative stress. Resveratrol (RES) is a bioactive antioxidant compound to combat oxidative damage. However, its role in the protection of HG-induced osteoblast dysfunction has not been clarified. Therefore, our study aimed to explore potential regulatory mechanisms of RES for attenuating HG-induced osteoblast dysfunction. Our results showed that osteoblast dysfunction under HG condition was significantly ameliorated by RES via the activation of nuclear factor erythroid 2-related factor (NRF2) to suppress oxidative stress. Furthermore, using Nrf2-shRNA and wortmannin, we identified that activation of NRF2 via RES was regulated by the AKT/glycogen synthase kinase 3ß (GSK3ß)/FYN axis.

Cardiac SIRT1 ameliorates doxorubicin-induced cardiotoxicity by targeting sestrin 2.

Although it is known that the expression and activity of sirtuin 1 (SIRT1) significantly decrease in doxorubicin (DOX)-induced cardiomyopathy, the role of interaction between SIRT1 and sestrin 2 (SESN2) is largely unknown. In this study, we investigated whether SESN2 could be a crucial target of SIRT1 and the effect of their regulatory interaction and mechanism on DOX-induced cardiac injury. Here, using DOX-treated cardiomyocytes and cardiac-specific Sirt1 knockout mice models, we found SIRT1 deficiency aggravated DOX-induced cardiac structural abnormalities and dysfunction, whereas the activation of SIRT1 by resveratrol (RES) treatment or SIRT1 overexpression possessed cardiac protective effects. Further studies indicated that SIRT1 exerted these beneficial effects by markedly attenuating DOX-induced oxidative damage and apoptosis in a SESN2-dependent manner. Knockdown of Sesn2 impaired RES/SIRT1-mediated protective effects, while upregulation of SESN2 efficiently rescued DOX-induced oxidative damage and apoptosis. Most importantly, SIRT1 activation could reduce DOX-induced SESN2 ubiquitination possibly through reducing the interaction of SESN2 with mouse double minute 2 (MDM2). The recovery of SESN2 stability in DOX-impaired primary cardiomyocytes by SIRT1 was confirmed by Mdm2-siRNA transfection. Taken together, our findings indicate that disrupting the interaction between SESN2 and MDM2 by SIRT1 to reduce the ubiquitination of SESN2 is a novel regulatory mechanism for protecting hearts from DOX-induced cardiotoxicity and suggest that the activation of SIRT1-SESN2 axis has potential as a therapeutic approach to prevent DOX-induced cardiotoxicity.

Anti-influenza mechanism of phenolic phytochemicals from Canarium album (Lour.) DC. leaf extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Canarium album (Lour.) DC. belongs to the Burseraceae family. Its leaf, named as Ganlanye (GLY), was recorded to treat warm disease symptoms via clearing lung heat and toxicants in medical classics. Its aqueous extract had anti-influenza activity in our previous phenotypic screening. However, its active components and mechanism were not identified. AIM: We aim to isolate the anti-influenza phytochemicals from GLY extract and explore its anti-flu mechanism. MATERIAL AND METHODS: Influenza A virus infected MDCK cells were used to test the compounds and fractions. Structural analyses of new compounds were performed via NMR calculation with the combination of DP4plus probability method and computed electronic circular dichroism (ECD). Hemagglutination inhibitory assay and neuraminidase inhibitory assay were performed to find the target protein. Molecular docking and recombinant virus were used to confirm the action site of the three new canaroleosides. RESULTS: Three new phenolic glycosides, canaroleosides A-C (1-3), and three known flavonoids (4-6), were isolated from the GLY aqueous extract and their anti-influenza virus mechanism was revealed. The absolute configurations of 1-3 were determined by ECD method, with the structure of the 2,5-dihydroxybenzoic acid moiety in 1 assigned by NMR calculation. Compound 1 was found to suppress both hemagglutinin and neuraminidase activities. Compounds 2, 3 4 and 6 inhibited neuraminidase, while compound 5 inhibited hemagglutinin. 1-3 could interact with Arg152 of the viral neuraminidase based on the result of molecular docking and reverse genetics. CONCLUSION: Six phytochemicals were isolated from GLY aqueous extract and found to inhibit influenza A strains. They were found to interact with hemagglutinin or neuraminidase and canaroleosides 1-3 could interact with Arg152 of the viral neuraminidase. This study provided more evidence on the anti-influenza effect of Ganlan and laid the foundation for further generation of potent NA inhibitors.

Novel mechanistic insight on the neuroprotective effect of berberine: The role of PPARδ for antioxidant action.

Cerebral ischemic stroke ranks the second leading cause of death and the third leading cause of disability in lifetime all around the world, urgently necessitating effective therapeutic interventions. Reactive oxygen species (ROS) have been implicated in stroke pathogenesis and peroxisome proliferator-activated receptors (PPARs) are prominent targets for ROS management. Although recent research has shown antioxidant effect of berberine (BBR), little is known regarding its effect upon ROS-PPARs signaling in stroke. The aim of this study is to explore whether BBR could target on ROS-PPARs pathway to ameliorate middle cerebral artery occlusion (MCAO)-induced stroke. Herein, we report that BBR is able to scavenge ROS in oxidation-damaged C17.2 neural stem cells and stroked mice. PPARδ, rather than PPARα or PPARγ, is involved in the anti-ROS effect of BBR, as evidenced by the siRNA transfection and specific antagonist treatment data. Further, we have found BBR could upregulate NF-E2 related factor-1/2 (NRF1/2) and NAD(P)H:quinone oxidoreductase 1 (NQO1) following a PPARδ-dependent manner. Mechanistic study has revealed that BBR acts as a potent ligand (Kd = 290 ± 92 nM) to activate PPARδ and initiates the transcriptional regulation functions, thus promoting the expression of PPARδ, NRF1, NRF2 and NQO1. Collectively, our results indicate that BBR confers neuroprotective effects by activating PPARδ to scavenge ROS, providing a novel mechanistic insight for the antioxidant action of BBR.