Omentin-1 ameliorates pulmonary arterial hypertension by inhibiting endoplasmic reticulum stress through AMPKα signaling.

BACKGROUND: Endothelial dysfunction of the pulmonary artery contributes to hypoxia-induced pulmonary arterial hypertension (PAH). Omentin-1, as a novel adipocytokine, plays an important protective role against cardiovascular diseases. However, the effect and underlying mechanisms of omentin-1 against PAH remain unclear. METHODS: PAH was induced in SD (Sprague & Dawley) rats via a low-oxygen chamber for 4 weeks. Hemodynamic evaluation was undertaken using a PowerLab data acquisition system, and histopathological analysis was stained with hematoxylin and eosin (H&E). Endothelial function of pulmonary artery was assessed using wire myography. RESULTS: We found that omentin-1 significantly improved pulmonary endothelial function in rats exposed to hypoxia and attenuated PAH. Mechanistically, we found that omentin-1 increased phosphorylated 5'­adenosine monophosphate­activated protein kinase (p­AMPK) level and reduced endoplasmic reticulum (ER) stress and increased NO production in pulmonary artery from rats exposed to hypoxia. However, the effect of omentin-1 was abolished by treatment with AMPK inhibitor (Compound C). CONCLUSIONS: Our results reveal a protective effect of omentin-1 in PAH via inhibiting ER stress through AMPKα signaling and provide an agent with translational potential for the treatment of PAH.

Natural products targeting macroautophagy signaling in hepatocellular carcinoma therapy: Recent evidence and perspectives.

Hepatocellular carcinoma (HCC), presently the second leading cause of global cancer-related mortality, continues to pose significant challenges in the realm of medical oncology, impacting both clinical drug selection and mechanistic research. Recent investigations have unveiled autophagy-related signaling as a promising avenue for HCC treatment. A growing body of research has highlighted the pivotal role of autophagy-modulating natural products in inhibiting HCC progression. In this context, we provide a concise overview of the fundamental autophagy mechanism and delineate the involvement of autophagic signaling pathways in HCC development. Additionally, we review pertinent studies demonstrating how natural products regulate autophagy to mitigate HCC. Our findings indicate that natural products exhibit cytotoxic effects through the induction of excessive autophagy, simultaneously impeding HCC cell proliferation by autophagy inhibition, thereby depriving HCC cells of essential energy. These effects have been associated with various signaling pathways, including PI3K/AKT, MAPK, AMPK, Wnt/ß-catenin, Beclin-1, and ferroautophagy. These results underscore the considerable therapeutic potential of natural products in HCC treatment. However, it is important to note that the present study did not establish definitive thresholds for autophagy induction or inhibition by natural products. Further research in this domain is imperative to gain comprehensive insights into the dual role of autophagy, equipping us with a better understanding of this double-edged sword in HCC management.

Azonia-Naphthalene: A Cationic Hydrophilic Building Block for Stable N-Type Organic Mixed Ionic-Electronic Conductors.

Conjugated polymers that can efficiently transport both ionic and electronic charges have broad applications in next-generation optoelectronic, bioelectronic, and energy storage devices. To date, almost all the conjugated polymers have hydrophobic backbones, which impedes efficient ion diffusion/transport in aqueous media. Here, we design and synthesize a novel hydrophilic polymer building block, 4a-azonia-naphthalene (AN), drawing inspiration from biological systems. Because of the strong electron-withdrawing ability of AN, the AN-based polymers show typical n-type charge transport behaviors. We find that cationic aromatics exhibit strong cation-π interactions, leading to smaller π-π stacking distance, interesting ion diffusion behavior, and good morphology stability. Additionally, AN enhances the hydrophilicity and ionic-electronic coupling of the polymer, which can help to improve ion diffusion/injection speed, and operational stability of organic electrochemical transistors (OECTs). The integration of cationic building blocks will undoubtedly enrich the material library for high-performance n-type conjugated polymers.

Natural products targeting signaling pathways associated with regulated cell death in gastric cancer: Recent advances and perspectives.

Gastric cancer (GC) is one of the most serious gastrointestinal malignancies with high morbidity and mortality. The complexity of GC process lies in the multi-phenotypic linkage regulation, in which regulatory cell death (RCD) is the core link, which largely dominates the fate of GC cells and becomes a key determinant of GC development and prognosis. In recent years, increasing evidence has been reported that natural products can prevent and inhibit the development of GC by regulating RCDs, showing great therapeutic potential. In order to further clarify its key regulatory characteristics, this review focused on specific expressions of RCDs, combined with a variety of signaling pathways and their crosstalk characteristics, sorted out the key targets and action rules of natural products targeting RCD. It is highlighted that a variety of core biological pathways and core targets are involved in the decision of GC cell fate, including the PI3K/Akt signaling pathway, MAPK-related signaling pathways, p53 signaling pathway, ER stress, Caspase-8, gasdermin D (GSDMD), and so on. Moreover, natural products target the crosstalk of different RCDs by modulating above signaling pathways. Taken together, these findings suggest that targeting various RCDs in GC with natural products is a promising strategy, providing a reference for further clarifying the molecular mechanism of natural products treating GC, which warrants further investigations in this area.

Using POI and time series Landsat data to identify and rebuilt surface mining, vegetation disturbance and land reclamation process based on Google Earth Engine.

The development of coal resources is necessary, but it has a huge negative impact on land, ecology, and the environment. With the increasing awareness of environmental protection and the requirements of related regulations, the design and practice of reclamation projects run through the mining life cycle and continue for a long time after the coal production. High-precision monitoring of mining disturbance and reclamation, quantifying the degree and time of vegetation disturbance and restoration, is of great significance to minimize the environmental effect of mining. Remote sensing, widely used as efficient monitoring tool, but there is not enough research on disturbance and reclamation monitoring taking into account large-scale areas and high temporal and spatial accuracy. Especially when mining sites remain unknown, how to distinguish the disturbance of coal mining and other human activities affecting the surface land cover has become a challenge. Therefore, this paper proposed a method to reconstruct the time series of mining disturbance and reclamation in a large area by using the POI (point of interest) and Landsat time series images using multiple buffer analysis methods. The process includes: (1) Retrieval of POI in the study area based on the public mining list using Python crawler, and buffering 100 km for preliminary extraction of potential mining areas; (2) Using spectral index mask and random forest algorithm to accurately extract the exposed coal on the Google Earth Engine (GEE) platform; (3) Buffering 10 km to identify the occurrence of disturbance and reclamation, using pixel-based temporal trajectory identification of LandTrendr algorithm under GEE. The method successful detect the change points of surface coal mining disturbance and reclamation in eastern Inner Mongolia of China. The results show that: (1) The method can effectively identify the extent of surface coal mining disturbance and reclamation, and the overall extraction accuracy is 81%. (2) Surface coal mining disturbance in eastern Inner Mongolia was concentrated in 2006-2011. By 2020, the total disturbed area is 627.8 km2, with an average annual disturbance of 18.5 km2, and the annual maximum disturbance to the ground reached 64.6 km2 in 2008. With the total reclaimed area being 236.3 km2, the reclamation rate is about 37.6%. This study provides a systematic solution and process for monitoring the disturbance and reclamation of surface coal mining in a large range with little known about the mines' location. It can effectively identify the mining disturbance and reclamation process which can also be extended to other areas, providing a quantitative assessment of mining disturbance and reclamation, which can support further ecological restoration decision-making.

Single-dose rAAV5-based vaccine provides long-term protective immunity against SARS-CoV-2 and its variants.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus and its variants, has posed unprecedented challenges worldwide. Existing vaccines have limited effectiveness against SARS-CoV-2 variants. Therefore, novel vaccines to match mutated viral lineages by providing long-term protective immunity are urgently needed. We designed a recombinant adeno-associated virus 5 (rAAV5)-based vaccine (rAAV-COVID-19) by using the SARS-CoV-2 spike protein receptor binding domain (RBD-plus) sequence with both single-stranded (ssAAV5) and self-complementary (scAAV5) delivery vectors and found that it provides excellent protection from SARS-CoV-2 infection. A single-dose vaccination in mice induced a robust immune response; induced neutralizing antibody (NA) titers were maintained at a peak level of over 1:1024 more than a year post-injection and were accompanied by functional T-cell responses. Importantly, both ssAAV- and scAAV-based RBD-plus vaccines produced high levels of serum NAs against the circulating SARS-CoV-2 variants, including Alpha, Beta, Gamma and Delta. A SARS-CoV-2 virus challenge showed that the ssAAV5-RBD-plus vaccine protected both young and old mice from SARS-CoV-2 infection in the upper and lower respiratory tracts. Whole genome sequencing demonstrated that AAV vector DNA sequences were not found in the genomes of vaccinated mice one year after vaccination, demonstrating vaccine safety. These results suggest that the rAAV5-based vaccine is safe and effective against SARS-CoV-2 and several variants as it provides long-term protective immunity. This novel vaccine has a significant potential for development into a human prophylactic vaccination to help end the global pandemic.

Old wine in new bottles: Kaempferol is a promising agent for treating the trilogy of liver diseases.

As a source of various compounds, natural products have long been important and valuable for drug development. Kaempferol (KP) is the most common flavonol with bioactive activity and has been extracted from many edible plants and traditional Chinese medicines. It has a wide range of pharmacological effects on inflammation, oxidation, and tumour and virus regulation. The liver is an important organ and is involved in metabolism and activity. Because the pathological process of liver diseases is extremely complicated, liver diseases involving ALD, NASH, liver fibrosis, and HCC are often complicated and difficult to treat. Fortunately, there have been many reports that KP has a good pharmacological effect on a series of complex liver diseases. To fully understand the mechanism of KP and provide new ideas for its clinical application in the treatment of liver diseases, this article reviews the pharmacological mechanism and potential value of KP in different studies involving various liver diseases. In the trilogy of liver disease, high concentrations of ROS stimulate peroxidation and activate the inflammatory signal cascade, which involves signalling pathways such as MAPK/JAK-STAT/PERK/Wnt/Hipp, leading to varying degrees of cell degradation and liver damage. The development of liver disease is promoted in an inflammatory environment, which is conducive to the activation of TGF-ß1, leading to increased expression of pro-fibrosis and pro-inflammatory genes. Inflammation and oxidative stress promote the formation of tumour microenvironments, and uncontrolled autophagy of cancer cells further leads to the development of liver cancer. The main pathway in this process is AMPK/PTEN/PI3K-Akt/TOR. KP can not only protect liver parenchymal cells through a variety of antioxidant and anti-apoptotic mechanisms but also reduces the immune inflammatory response in the liver microenvironment, thereby preventing cell apoptosis; it can also inhibit the ER stress response, prevent inflammation and inhibit tumour growth. KP exerts multiple therapeutic effects on liver disease by regulating precise signalling targets and is expected to become an emerging therapeutic opportunity to treat liver disease in the future.

Efficacy and safety of endovascular treatment with or without intravenous alteplase in acute anterior circulation large vessel occlusion stroke: a meta-analysis of randomized controlled trials.

OBJECTIVE: The current meta-analysis aimed to investigate the efficacy and safety of direct endovascular treatment (EVT) and bridging therapy (EVT with prior intravenous thrombolysis (IVT)) in patients with acute anterior circulation large vessel occlusion (LVO) stroke. METHODS: This meta-analysis followed PRISMA guidelines. Eligible RCTs were identified through a systemic search of electronic databases (PubMed, Ovid, Web of Science, and Cochrane Library) from the inception dates to January 10, 2022. The pooled analyses were performed using RevMan 5.3 software. The primary outcome was functional outcome on the modified Rankin Scale (mRS) (range 0 to 5) at 90 days. The secondary outcomes included successful reperfusion, intracranial hemorrhage, and mortality (mRS 6) within 90 days. RESULTS: A total of 4 RCTs involving 1633 patients were finally included. Findings of pooled analyses indicated that neither the primary outcomes (no disability (mRS 0), no significant disability despite some symptoms (mRS 1), slight disability (mRS 2), moderate disability (mRS 3), moderately severe disability (mRS 4), severe disability (mRS 5), excellent outcome (mRS 0-1), functional independence outcome (mRS 0-2), and poor outcome (mRS 3-5)) nor the secondary outcomes (successful reperfusion, intracranial hemorrhage, and mortality) in the EVT groups were not statistically significant compared with the IVT plus EVT groups (P > 0.05). In addition, the outcomes of sensitivity analysis implied that the findings of meta-analysis were credible. CONCLUSIONS: Among patients with acute ischemic stroke due to LVO of anterior circulation, EVT alone yielded efficacy and safety outcomes similar to IVT plus EVT.

Paeoniflorin Protects against Acetaminophen-Induced Liver Injury in Mice via JNK Signaling Pathway.

BACKGROUND: Drug-induced liver injury (DILI), represented by acetaminophen (APAP), is a common cause of acute liver failure in clinics. Paeoniflorin (PF) has been proven to demonstrate a significant hepatoprotective effect. However, it is still unclear whether it can be a potential agent against hepatotoxicity induced by APAP. This study aimed to explore the preventive and therapeutic effects and mechanisms of PF on APAP-induced liver injury. METHODS: Different doses of PF (50, 100, and 200 mg/kg) were given to C57BL/6 male mice for five consecutive days. After 12 h of APAP (250 mg/kg i.p.) treatment, blood and liver tissues were collected and isolated for detection. RESULTS: The results showed that the therapeutic effects of PF on APAP mice were presented in the downregulation of the content of serum indices and significantly improved hepatic tissue edema and inflammatory infiltration. Meanwhile, PF reduces the level of the mitochondrial metabolic enzyme. Ulteriorly, it was found that PF has a downregulating effect on the apoptotic reaction and could inhibit the protein expression of CYP2E1/JNK signaling, which in turn reduces the damage of APAP. CONCLUSION: Our findings showed that PF acted as a protective agent against APAP-induced hepatotoxicity by inhibiting JNK-related signals, suggesting a novel insight into treating APAP-induced liver injury.

Diagnostic value of peripheral hematologic markers for coronavirus disease 2019 (COVID-19): A multicenter, cross-sectional study.

BACKGROUND: To determine the diagnostic value of hematologic markers for coronavirus disease 2019 (COVID-19) and explore their relationship with disease severity. METHODS: Subjects included 190 COVID-19 patients, 190 healthy subjects, and 105 influenza pneumonia (IP) patients. COVID-19 patients were divided into the ARDS and non-ARDS groups. Routine blood examination, biochemistry indicator, days in hospital, body temperature, pneumonia severity index (PSI), CURB-65, and MuLBSTA were recorded. Correlations between variables were assessed using Spearman's correlation analysis. Receiver operating characteristic (ROC) curves were used to study the accuracy of the various diagnostic tests. RESULTS: Compared with healthy subjects, COVID-19 patients had lower white blood cell (WBC), lymphocyte, platelet, and hemoglobin levels; higher percentages of neutrophils and monocytes; lower percentages of lymphocytes and higher neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) values (P < .05). COVID-19 patients had higher WBC and neutrophil levels and lower percentages of lymphocytes compared to IP (P < .05). ROC curve analysis revealed that MLR had a high diagnostic value in differentiating COVID-19 patients from healthy subjects, but not from IP patients. NLR showed significant positive correlations with PSI, CURB-65, and MuLBSTA. Lymphocyte count was lower in the ARDS group and yielded a higher diagnostic value than the other variables. CONCLUSIONS: Monocyte-to-lymphocyte ratio showed an acceptable efficiency to separate COVID-19 patients from healthy subjects, but failed to rule out IP patients. NLR may be a reliable marker to evaluate the disease severity of COVID-19. Lymphocyte count may be useful to establish the early diagnosis of ARDS in the COVID-19 patients.

Rosiglitazone promotes ENaC-mediated alveolar fluid clearance in acute lung injury through the PPARγ/SGK1 signaling pathway.

BACKGROUND: Pulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS). The epithelial sodium channel (ENaC) is thought to be the rate-limiting factor for alveolar fluid clearance (AFC) during pulmonary edema. The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone was shown to stimulate ENaC-mediated salt absorption in the kidney. However, its role in the lung remains unclear. Here, we investigated the role of the PPARγ agonist in the lung to find out whether it can regulate AFC during acute lung injury (ALI). We also attempted to elucidate the mechanism for this. METHODS: Our ALI model was established through intratracheal instillation of lipopolysaccharide (LPS) in C57BL/6 J mice. The mice were randomly divided into 4 groups of 10. The control group underwent a sham operation and received an equal quantity of saline. The three experimental groups underwent intratracheal instillation of 5 mg/kg LPS, followed by intraperitoneal injection of 4 mg/kg rosiglitazone, 4 mg/kg rosiglitazone plus 1 mg/kg GW9662, or only equal quantity of saline. The histological morphology of the lung, the levels of TNF-α and IL-1ß in the bronchoalveolar lavage fluid (BALF), the level of AFC, and the expressions of αENaC and serum and glucocorticoid-induced kinase-1 (SGK1) were determined. Type 2 alveolar (AT II) cells were incubated with rosiglitazone (15 µM) with or without GW9662 (10 µM). The expressions of αENaC and SGK1 were determined 24 h later. RESULTS: A mouse model of ALI was successfully established. Rosiglitazone significantly ameliorated the lung injury, decreasing the TNF-α and IL-1ß levels in the BALF, enhancing AFC, and promoting the expressions of αENaC and SGK1 in ALI mice, which were abolished by the specific PPARγ blocker GW9662. In vitro, rosiglitazone increased the expressions of αENaC and SGK1. This increase was prevented by GW9662. CONCLUSIONS: Rosiglitazone ameliorated the lung injury and promoted ENaC-mediated AFC via a PPARγ/SGK1-dependent signaling pathway, alleviating pulmonary edema in a mouse model of ALI.

Curcumin Attenuates Asthmatic Airway Inflammation and Mucus Hypersecretion Involving a PPARγ-Dependent NF-κB Signaling Pathway In Vivo and In Vitro.

Asthma is characterized by airway inflammation and mucus hypersecretion. Curcumin possessed a potent anti-inflammatory property involved in the PPARγ-dependent NF-κB signaling pathway. Then, the aim of the current study was to explore the value of curcumin in asthmatic airway inflammation and mucus secretion and its underlying mechanism. In vivo, mice were sensitized and challenged by ovalbumin (OVA) to induce chronic asthma. Airway inflammation and mucus secretion were analyzed. In vitro, BEAS-2B cells were obtained. MCP-1, MUC5AC, and PPARγ expression and the phosphorylation of NF-κB p65 and NF-κB p65 DNA-binding activity were measured in both the lungs and BEAS-2B cells. shRNA-PPARγ was used to knock down PPARγ expression. We found that OVA-induced airway inflammation and mucus hypersecretion in mice, OVA and IL-4-induced upregulation of MCP-1 and MUC5AC, suppression of PPARγ, and activation and translocation of NF-κB p65 were notably improved by curcumin both in vivo and in vitro. Our data also showed that these effects of curcumin were significantly abrogated by shRNA-PPARγ. Taken together, our results indicate that curcumin attenuated OVA-induced airway inflammation and mucus hypersecretion in mice and suppressed OVA- and IL-4-induced upregulation of MCP-1 and MUC5AC both in vivo and in vitro, most likely through a PPARγ-dependent NF-κB signaling pathway.

Enzymatic determination of uric acid using water-soluble CuInS/ZnS quantum dots as a fluorescent probe.

Glutathione-capped water-soluble CuInS/ZnS quantum dots (QDs) were prepared by a microwave-assisted method. Their fluorescence, with excitation/emission peaks at 380/570 nm, is found to be quenched by hydrogen peroxide (H2O2) that is produced by the uricase catalyzed oxidation of uric acid (UA) and oxygen. The findings are used in a quenchometric method for the determination of UA. The effects of different ligands on the QDs, of pH value, buffers, enzyme ratio and reaction time were optimized. The detection limit for UA is 50 nM which is lower than other QD-based method, and the detection ranges extends from 0.25-4.0 µM. The assay is simple and sensitive, and no further modification of the QDs is required. Graphical abstract ᅟ.

CD151 restricts the α6 integrin diffusion mode.

Laminin-binding integrins (α3ß1, α6ß1, α6ß4, α7ß1) are almost always expressed together with tetraspanin CD151. In every coexpressing cell analyzed to date, CD151 makes a fundamental contribution to integrin-dependent motility, invasion, morphology, adhesion and/or signaling. However, there has been minimal mechanistic insight into how CD151 affects integrin functions. In MDA-MB-231 mammary cells, tetraspanin CD151 knockdown impairs α6 integrin clustering and functions without decreasing α6 integrin expression or activation. Furthermore, CD151 knockdown minimally affects the magnitude of α6 integrin diffusion, as measured using single particle tracking. Instead, CD151 knockdown has a novel and unexpected dysregulating effect on the mode of α6 integrin diffusion. In control cells α6 integrin shows mostly random-confined diffusion (RCD) and some directed motion (DMO). In sharp contrast, in CD151-knockdown cells α6 integrin shows mostly DMO. In control cells α6 diffusion mode is sensitive to actin disruption, talin knockdown and phorbol ester stimulation. By contrast, CD151 knockdown cell α6 integrin is sensitive to actin disruption but desensitized to talin knockdown or phorbol ester stimulation, indicating dysregulation. Both phorbol ester and EGF stimulate cell spreading and promote α6 RCD in control cells. By contrast, CD151-ablated cells retain EGF effects but lose phorbol-ester-stimulated spreading and α6 RCD. For α6 integrins, physical association with CD151 promotes α6 RCD, in support of α6-mediated cable formation and adhesion. By comparison, for integrins not associated with CD151 (e.g. αv integrins), CD151 affects neither diffusion mode nor αv function. Hence, CD151 support of α6 RCD is specific and functionally relevant, and probably underlies diverse CD151 functions in skin, kidney and cancer cells.

The occurrence of asthma in an extensive-stage small-cell lung cancer patient after combination therapy with atezolizumab and anlotinib: a case report.

Background: Extensive-stage small-cell lung cancer (ES-SCLC) is highly malignant, with early metastasis and high recurrence. Since therapeutic options are limited, ES-SCLC has a characteristically short survival period and extremely poor prognosis. A combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs can achieve promising efficacy and safety in patients with ES-SCLC as a second-line or subsequent treatment, extending survival to some extent. However, the clinical outcomes remain mostly unsatisfactory and are sometimes affected by treatment-related adverse events. Case presentation: A 57-year-old woman with ES-SCLC was administered a combination therapy of atezolizumab (a PD-L1 inhibitor) and anlotinib [an oral multi-targeted tyrosine kinase inhibitor (TKI)]. She survived for 22 months, with no disease progression during the 28 courses of therapy. Unexpectedly, despite having no history of asthma, the patient developed asthma while receiving this regimen. This is possibly related to T-cell activation and the tumor immune microenvironment, which induce allergic inflammation after PD-L1 blockade. Conclusions: This is the first report of an asthma-negative ES-SCLC patient who developed asthma after receiving atezolizumab plus anlotinib. Although this combination therapy may effectively extend survival in SCLC patients, asthmatic symptoms should be closely monitored.

Protective role of curcumin in disease progression from non-alcoholic fatty liver disease to hepatocellular carcinoma: a meta-analysis.

Background: Pathological progression from non-alcoholic fatty liver disease (NAFLD) to liver fibrosis (LF) to hepatocellular carcinoma (HCC) is a common dynamic state in many patients. Curcumin, a dietary supplement derived from the turmeric family, is expected to specifically inhibit the development of this progression. However, there is a lack of convincing evidence. Methods: The studies published until June 2023 were searched in PubMed, Web of Science, Embase, and the Cochrane Library databases. The SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) approach was used to evaluate the certainty of evidence. StataSE (version 15.1) and Origin 2021 software programs were used to analyze the critical indicators. Results: Fifty-two studies involving 792 animals were included, and three disease models were reported. Curcumin demonstrates a significant improvement in key indicators across the stages of NAFLD, liver fibrosis, and HCC. We conducted a detailed analysis of common inflammatory markers IL-1ß, IL-6, and TNF-α, which traverse the entire disease process. The research results reveal that curcumin effectively hinders disease progression at each stage by suppressing inflammation. Curcumin exerted hepatoprotective effects in the dose range from 100 to 400 mg/kg and treatment duration from 4 to 10 weeks. The mechanistic analysis reveals that curcumin primarily exerts its hepatoprotective effects by modulating multiple signaling pathways, including TLR4/NF-κB, Keap1/Nrf2, Bax/Bcl-2/Caspase 3, and TGF-ß/Smad3. Conclusion: In summary, curcumin has shown promising therapeutic effects during the overall progression of NAFLD-LF-HCC. It inhibited the pathological progression by synergistic mechanisms related to multiple pathways, including anti-inflammatory, antioxidant, and apoptosis regulation.

Paeonia lactiflora Pall. ameliorates acetaminophen-induced oxidative stress and apoptosis via inhibiting the PKC-ERK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeonia lactiflora Pall. (PLP), a traditional Chinese medicine, is recognized for its antioxidative and anti-apoptotic properties. Despite its potential medicinal value, the mechanisms underlying its efficacy have been less explored, particularly in alleviating acute liver injury (ALI) caused by excessive intake of acetaminophen (APAP). AIM OF THE STUDY: This study aims to elucidate the role and mechanisms of PLP in mitigating oxidative stress and apoptosis induced by APAP. MATERIALS AND METHODS: C57BL/6 male mice were pre-treated with PLP for seven consecutive days, followed by the induction of ALI using APAP. Liver pathology was assessed using HE staining. Serum indicators, immunofluorescence (IF), immunohistochemical (IHC), and transmission electron microscopy were employed to evaluate levels of oxidative stress, ferroptosis and apoptosis. Differential expression proteins (DEPs) in the APAP-treated and PLP pre-treated groups were analyzed using quantitative proteomics. Subsequently, the potential mechanisms of PLP pre-treatment in treating ALI were validated using western blotting, molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) analysis. RESULTS: The UHPLC assay confirmed the presence of three compounds, i.e., albiflorin, paeoniflorin, and oxypaeoniflorin. Pre-treatment with PLP was observed to ameliorate liver tissue pathological damage through HE staining. Further confirmation of efficacy of PLP in alleviating APAP-induced liver injury and oxidative stress was established through liver function serum biochemical indicators, IF of reactive oxygen species (ROS) and IHC of glutathione peroxidase 4 (GPX4) detection. However, PLP did not demonstrate a significant effect in alleviating APAP-induced ferroptosis. Additionally, transmission electron microscopy and TUNEL staining indicated that PLP can mitigate hepatocyte apoptosis. PKC-ERK pathway was identified by proteomics, and subsequent molecular docking, molecular dynamics simulations, and SPR verified binding of the major components of PLP to ERK protein. Western blotting demonstrated that PLP suppressed protein kinase C (PKC) phosphorylation, blocking extracellular signal-regulated kinase (ERK) phosphorylation and inhibiting oxidative stress and cell apoptosis. CONCLUSION: This study demonstrates that PLP possesses hepatoprotective abilities against APAP-induced ALI, primarily by inhibiting the PKC-ERK cascade to suppress oxidative stress and cell apoptosis.

Optimized therapeutic potential of Yinchenhao decoction for cholestatic hepatitis by combined network meta-analysis and network pharmacology.

BACKGROUND: Cholestatic hepatitis is recognized as a significant contributor to the development of liver fibrosis and cirrhosis. As a well-known classic formula for the treatment of cholestatic hepatitis, Yinchenhao decoction (YCHD) is widely used in countries in Asia, including China, Japan, and Korea. However, in recent years, a risk of liver injury has been reported from Rheum palmatum L. and Gardenia jasmonoides J.Ellis which are the main ingredients of YCHD. Therefore, the question arises whether YCHD is still safe enough for the treatment of cholestatic hepatitis or whether an optimized ratio of ingredients should be applied. These is inevitable questions for the clinical application of YCHD. PURPOSE: To provide a scientific basis for the clinical application of YCHD through a combination of meta-analysis and network pharmacology and to find the best ratio of components to ensure optimal therapeutic efficacy and safety. At the same time, a deeper understanding of the mechanisms of YCHD was explored. METHODS: We retrieved relevant trials from various databases including PubMed, Web of Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP and Wanfang databases up to August 2023. After screening for inclusion and exclusion criteria, we assessed efficiency, ALT, AST, and TBIL as outcome parameters. The relevant data underwent a network meta-analysis using STATA 16.0 software. Based on network pharmacology, we screened the disease targets, active ingredients, and targets related to YCHD. The targets were visualized using Cytoscape 3.9.1. Then, potential mechanisms were explored based on bioinformatic techniques. RESULTS: Twenty eligible studies were finally screened and a total of 1,591 patients who fulfilled the inclusion criteria were enrolled in the study. The meta-analysis results indicated that TG-c (treatment group c) [(Artemisia capillaris Thunb. : Gardenia jasminoides J.Ellis : Rheum palmatum L. = 10:5:2-10:5:3) + CT] was the most promising therapeutic approach, demonstrating superior efficacy and notable improvements in both AST and TBIL levels. For ALT, TG-d [(Artemisia capillaris : Gardenia jasminoides : Rheum palmatum = 5:1:1-5:2:1) + CT] exhibited the greatest potential as optimal therapy option. Based on the surface under the cumulative ranking curve (SUCRA) values, TG-c was the best therapy in terms of efficiency and improvement in TBIL levels, while TG-d was the most effective in reducing ALT levels. For AST levels, TG-e [(Artemisia capillaris : Gardenia jasminoides : Rheum palmatum = 5:2:2-5:3:3) + CT] was the most effective therapy. The comprehensive analysis revealed that TG-c exhibited the most pronounced efficacy. Combined network pharmacology, GO enrichment analysis and KEGG pathway enrichment analysis displayed that the key target genes of Artemisia capillaris, Rheum palmatum, and Gardenia jasminoides were closely involved in inflammation response, bile transport, apoptosis, oxidative stress, and regulation of leukocyte migration. Notably, bile secretion dominated the common pathway of the three herbs. On the other hand, Artemisia capillaris exhibited a unique mode of action by regulating the IL-17 signaling pathway, which may play a crucial role in its effectiveness. CONCLUSION: Based on our findings, the optimal TG-C demonstrated the most favorable overall therapeutic efficacy by increasing the dosage of Artemisia capillaris while reducing the dosage of Gardenia jasminoides and Rheum palmatum. This is attributed to the potent ability of Artemisia capillaris. to effectively modulate the IL-17 signaling pathway, thereby exerting a beneficial therapeutic effect. Conversely, Gardenia jasminoides and Rheum palmatum may potentially enhance the activation of the NF-кB signaling pathway, thereby elevating the risk of hepatotoxicity.

Continuous production of ultratough semiconducting polymer fibers with high electronic performance.

Conjugated polymers have demonstrated promising optoelectronic properties, but their brittleness and poor mechanical characteristics have hindered their fabrication into durable fibers and textiles. Here, we report a universal approach to continuously producing highly strong, ultratough conjugated polymer fibers using a flow-enhanced crystallization (FLEX) method. These fibers exhibit one order of magnitude higher tensile strength (>200 megapascals) and toughness (>80 megajoules per cubic meter) than traditional semiconducting polymer fibers and films, outperforming many synthetic fibers, ready for scalable production. These fibers also exhibit unique strain-enhanced electronic properties and exceptional performance when used as stretchable conductors, thermoelectrics, transistors, and sensors. This work not only highlights the influence of fluid mechanical effects on the crystallization and mechanical properties of conjugated polymers but also opens up exciting possibilities for integrating these functional fibers into wearable electronics.

Counterion docking: a general approach to reducing energetic disorder in doped polymeric semiconductors.

Molecular doping plays an important role in controlling the carrier concentration of organic semiconductors. However, the introduction of dopant counterions often results in increased energetic disorder and traps due to the molecular packing disruption and Coulomb potential wells. To date, no general strategy has been proposed to reduce the counterion-induced structural and energetic disorder. Here, we demonstrate the critical role of non-covalent interactions (NCIs) between counterions and polymers. Employing a computer-aided approach, we identified the optimal counterions and discovered that NCIs determine their docking positions, which significantly affect the counterion-induced energetic disorder. With the optimal counterions, we successfully reduced the energetic disorder to levels even lower than that of the undoped polymer. As a result, we achieved a high n-doped electrical conductivity of over 200 S cm-1 and an eight-fold increase in the thermoelectric power factor. We found that the NCIs have substantial effects on doping efficiency, polymer backbone planarity, and Coulomb potential landscape. Our work not only provides a general strategy for identifying the most suitable counterions but also deepens our understanding of the counterion effects on doped polymeric semiconductors.