Acute toxicity appraisal of Saussurea heteromalla extract and development of its chemotherapeutic herbal dosage form.

Ethnopharmacological relevance of Saussurea species for anti-cancer compounds instigated us to develop chemotherapeutic herbal tablets. This study was an ongoing part of our previous research based on the scientific evaluation of Saussurea heteromalla (S. heteromalla) for anti-cancer lead compounds. In the current study, S. heteromalla herbal tablets (500 /800 mg) were designed and evaluated for anti-cancer activity. Arctigenin was found as a bioactive lead molecule with anti-cancer potential for cervical cancer. The in vitro results on the HeLa cell line supported the ethnopharmacological relevance and traditional utilization of S. heteromalla and provided the scientific basis for the management of cervical cancer as proclaimed by traditional practitioners in China. LD50 of the crude extract was established trough oral acute toxicity profiling in mice, wherein the minimum lethal dose was noticed as higher than 1000 mg/kg body weight orally. Chromatographic fingerprint analysis ensured the identity and consistency of S. heteromalla in herbal tablets in terms of standardization of the herbal drug. About 99.15% of the drug (S. heteromalla crude extract) was recovered in herbal tablets (RSD: 0.45%). In vitro drug release profile was found to be more than 87% within 1 h, which was also correlated with different mathematical kinetic models of drug release (r2 = 0.992), indicating that drug release from matrix tablets into the blood is constant throughout the delivery. The dosage form was found stable after an accelerated stability parameters study which may be used for anti-cervical cancer therapy in the future, if it qualifies successful preclinical investigation parameters.

Impact of public-private partnerships investment and FDI on CO2 emissions: A study of six global investment countries.

This study investigates the impact of public-private partnerships investment in energy and FDI on environmental quality in global investment countries during 1995-2018. Economic growth, technological innovations and consumption of clean energy are also considered as additional determinants of environmental quality. The study applied advanced panel econometric models. Our empirical results affirm the evidence of a long-run association between environmental quality and its determinants. Specifically, economic growth as well as clean energy use improves quality of environment by lowering carbon emissions. Public-private partnerships investment in energy, FDI and technological innovations decrease carbon emissions. Energy consumption (generated from fossil fuel) increases carbon emissions. Heterogeneous causality evidence indicates the presence of a unidirectional causality relation from carbon emissions to public-private partnerships investment in energy and a feedback causality occurs between consumption of clean energy and CO2 emissions. This empirical evidence provides new insights for both policymakers and governments to support public-private partnership investments in energy for the improvement of quality of environment in global investment countries.

Geraniol Suppresses Oxidative Stress, Inflammation, and Interstitial Collagenase to Protect against Inflammatory Arthritis.

Geraniol (GER) is a plant-derived acyclic isoprenoid monoterpene that has displayed anti-inflammatory effects in numerous in vivo and in vitro models. This study was therefore designed to evaluate the antiarthritic potential of GER in complete Freund's adjuvant (CFA)-induced inflammatory arthritis (IA) model in rats. IA was induced by intraplantar injection of CFA (0.1 mL), and a week after CFA administration, rats were treated with various doses of methotrexate (MTX; 1 mg/kg) or GER (25, 50, and 100 mg/kg). Treatments were given on every alternate day, and animals were sacrificed on the 35th day. Paw volume, histopathological, hematological, radiographic, and qPCR analyses were performed to analyze the severity of the disease. GER significantly reduced paw edema after 35 days of treatment, and these results were comparable to the MTX-treated group. GER-treated animals displayed a perfect joint structure with minimal inflammation and no signs of cartilage or bone damage. Moreover, GER restored red blood cell and hemoglobin levels, normalized erythrocyte sedimentation rate, platelet, and c-reactive protein values, and also attenuated the levels of rheumatoid factor. RT-qPCR analysis demonstrated that GER decreased mRNA expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta. GER also down-regulated the transcript levels of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1, prostaglandin D2 synthase, and interstitial collagenase (MMP-1). Molecular docking of GER with COX-2, TNF-α, and MMP-1 also revealed that the antiarthritic effects of GER could be due to its direct interactions with these mediators. Based on our findings, it is conceivable that the antiarthritic effects of GER could be attributed to downregulation of pro-inflammatory mediators and protease like MMP-1.

The Protective Effect of Citronellol against Doxorubicin-Induced Cardiotoxicity in Rats.

Citronellol has been reported to have anti-inflammatory, anti-cancer, and antihypertensive activities, but its effect on myocardial ischemia is still unclear. The aim of this study was to investigate the therapeutic effects and pharmacological mechanisms of citronellol on ischemia. Therefore, a rat model of myocardial ischemia was established using the doxorubicin (DOX) model. To induce cardiotoxicity, the rats were given DOX (2.5 mg/kg) intraperitoneally over a 14-day period. Group I served as the control and received tween 80 (0.2%), group II received the vehicle and DOX, group III received the standard drug dexrazoxane and DOX, whereas groups IV, V, and VI were treated orally with citronellol (25, 50, and 100 mg/kg) and DOX, respectively. After treatment, the rats were euthanized, and blood samples were collected to assess the levels of serum cardiac markers, lipid profiles, and tissue antioxidant enzymes. The gene expressions of eNOS, PPAR-g, IL-10, VEGF, and NFkB-1 were also determined using real-time polymerase chain reactions. Simultaneous treatment with DOX and citronellol reduced cardiac antioxidant enzymes and lipid biomarkers in a dose-dependent manner. Citronellol also increased the expression of anti-inflammatory cytokines while reducing the expression of pro-inflammatory cytokines. Therefore, it can be concluded that citronellol may have potential cardioprotective effects in preventing DOX-induced cardiotoxicity.

Imine Derivatives of Benzoxazole Attenuate High-Fat Diet-Induced Hyperlipidemia by Modulation of Lipid-Regulating Genes.

Purpose: Hyperlipidemia being the prominent risk factor of cardiovascular diseases and side effects associated with the current lipid-lowering drugs have attracted the interest of scientists in the quest for new alternatives. In view of the diverse pharmacological potentials of benzoxazole (BZX) compounds, this study was designed to evaluate the antihyperlipidemic activity of imine derivatives of BZX in high-fat diet (HFD)-fed rats. Methods: Hyperlipidemia was induced in Sprague-Dawley rats by using HFD for 28 days. On the 28th day, blood samples were collected, and animals having serum triglycerides (TG) greater than 400 mg/dL and total cholesterol (TC) greater than 280 mg/dL were selected for further study. Hyperlipidemic rats were daily treated with either a vehicle or simvastatin (SIM; 20 mg/kg) or BZX compounds (10, 20, and 30 mg/kg), for 12 consecutive days. After the specified time duration, hyperlipidemic biomarkers were evaluated in the blood samples of sacrificed rats. Liver samples were collected for histopathological and mRNA analyses. Binding affinities of BZX derivatives with different targets were assessed by molecular docking. Results: The present study revealed that the BZX derivatives dose-dependently reduced the serum levels of TC, TG, low-density lipoprotein, and very low-density lipoprotein along with improvement in high-density lipoprotein levels. Similarly, all the compounds reduced HFD-induced alanine transaminase and aspartate aminotransferase levels except BZX-4. Histopathology of liver samples demonstrated mild to moderate fatty changes upon treatment with BZX-1, BZX-2, and BZX-4. The hepatic architecture of the BZX-3-treated samples was close to normal, and only mild inflammation was witnessed in these samples. Moreover, all the compounds significantly increased superoxide dismutase and glutathione levels, indicating their antioxidant potentials. Gene expression data showed that BZX-1 and BZX-3 reduced lipid levels by inhibiting HMGCR, APOB, PCSK9, SRB1, and VCAM1 and via improving PPAR-α and APOE mRNA levels. BZX-2 demonstrated its antihyperlipidemic effects mainly due to inhibition of APOB, while BZX-4-mediated effects appeared to be due to attenuation of APOB, PCSK9, and SRB1. BZX derivatives displayed strong binding affinities with HMGCR, APOB, and VCAM1, which suggested that some of the interactions might be required for inhibition of these target proteins. Conclusions: Based on the current findings, it can be concluded that BZX derivatives exert their antihyperlipidemic effects via modulation of multiple lipid-regulating genes.

Pulegone Prevents Hypertension through Activation of Muscarinic Receptors and Cyclooxygenase Pathway in L-NAME-Induced Hypertensive Rats.

The current study was designed to determine pulegone's antihypertensive and vasoprotective activity in L-NAME-induced hypertensive rats. Firstly, the hypotensive dose-response relationship of pulegone was evaluated in normotensive anesthetized rats using the invasive method. Secondly, the mechanism involved in hypotensive activity was determined in the presence of pharmacological drugs such as atropine/muscarinic receptor blocker (1 mg/kg), L-NAME/NOS inhibitor (20 mg/kg), and indomethacin/COX inhibitor (5 mg/kg) in anesthetized rats. Furthermore, studies were carried out to assess the preventive effect of pulegone in L-NAME-induced hypertensive rats. Hypertension was induced in rats by administering L-NAME (40 mg/kg) orally for 28 days. Rats were divided into six groups which were treated orally with tween 80 (placebo), captopril (10 mg/kg), and different doses of pulegone (20 mg/kg, 40 mg/kg, and 80 mg/kg). Blood pressure, urine volume, sodium, and body weight were monitored weekly. After 28 days, the effect of pulegone on lipid profile, hepatic markers, antioxidant enzymes, and nitric oxide was estimated from the serum of treated rats. Moreover, plasma mRNA expression of eNOS, ACE, ICAM1, and EDN1 was measured using real-time PCR. Results show that pulegone dose-dependently decreased blood pressure and heart rate in normotensive rats, with the highest effect at 30 mg/kg/i.v. The hypotensive effect of pulegone was reduced in the presence of atropine and indomethacin, whereas L-NAME did not change its hypotensive effect. Concurrent treatment with pulegone for four weeks in L-NAME-treated rats caused a reduction in both systolic blood pressure and heart rate, reversed the reduced levels of serum nitric oxide (NO), and ameliorated lipid profile and oxidative stress markers. Treatment with pulegone also improved the vascular response to acetylcholine. Plasma mRNA expression of eNOS was reduced, whereas ACE, ICAM1, and EDN1 levels were high in the L-NAME group, which was facilitated by pulegone treatment. To conclude, pulegone prevented L-NAME-induced hypertension by demonstrating a hypotensive effect through muscarinic receptors and cyclooxygenase pathway, indicating its use as a potential candidate in managing hypertension.

Novel mannich-based derivative of 2-mercaptobenzimidazole (AK7): a new candidate for the treatment of inflammatory arthritis owing to its NF-κB1 inhibitory potential.

This study investigated the anti-arthritic potential of novel mannich-based derivatives of 2-mercaptobenzimidazole (AK7 and AK9) in rats. The compounds were characterized by NMR and FTIR spectroscopies and their acute anti-inflammatory effects were measured by carrageenan (CRG)-induced paw edema model. The most potent doses of AK7 and AK9 were subsequently evaluated in the complete Freund's adjuvant (CFA)-induced inflammatory arthritis model. AK7 and AK9 inhibited CRG-induced inflammation in a dose-dependent fashion and a similar reduction in CFA-induced paw inflammation was observed. Moreover, X-ray and histopathological analyses of AK7-treated animals displayed normal joint structure whereas AK9, despite of its anti-inflammatory effects, failed to protect against cartilage destruction. Interestingly, biochemical analysis revealed a better safety profile for AK7 than for AK9 and methotrexate. Both compounds suppressed mRNA levels of pro-inflammatory mediators (IRAK1, NF-κB1, TNF-α, IL1B) while only AK7 reduced the transcript levels of interstitial collagenase (MMP1). Molecular docking analysis of AK7 and AK9 with TNF-α and MMP1 also supported the experimental data. These findings clearly highlight the beneficial effects of AK7 in the prevention and/or treatment of inflammatory arthritis.

Empirical relationship between creativity and carbon intensity: a case of OPEC countries.

This article attempts to examine the role of creativity on carbon intensity in case of Organization of the Petroleum Exporting Countries (OPEC) countries. The panel estimation techniques are used for annual data for the period of 1990-2018. The empirical evidence affirms that patent rights and innovation act as a policy factor in controlling carbon intensity, i.e. creativity leads to energy-efficient and environment friendly society. However, innovations have higher magnitude compared to patent. Contrarily, urbanization and economic growth are the key determinants in enhancing carbon intensity, while renewable energy has insignificant impact on carbon intensity. The empirical analysis, especially for creativity, can add practical implications for related authorities in controlling carbon intensity and improving energy efficiency.

Amino Acid Conjugates of 2-Mercaptobenzimidazole Ameliorates High-Fat Diet-Induced Hyperlipidemia in Rats via Attenuation of HMGCR, APOB, and PCSK9.

PURPOSE: This study was designed to explore the antihyperlipidemic effects of amino acid derivatives of 2-mercaptobenzimidazole (4J and 4K) in high-fat diet (HFD)-fed rats. METHODS: Male Sprague-Dawley rats were divided into nine groups which received either standard diet or HFD for 28 days. Blood samples were taken on 27th day from HFD-fed rats to ensure hyperlipidemia. HFD-induced hyperlipidemic rats later received daily dosing of either vehicle or simvastatin (SIM; 20 mg/kg) or 4J/4K compounds (10, 20, and 30 mg/kg) for 12 consecutive days. On 40th day, animals were sacrificed, and blood samples were collected for the determination of serum lipid profile and liver function parameters. Liver samples were harvested for histopathological, antioxidant, and qPCR analyses. Molecular docking of tested compounds with HMGCR was also performed to assess the binding affinities. RESULTS: 4J and 4K dose dependently decreased serum total cholesterol, triglycerides, low-density lipoprotein, very low-density lipoproteins, alanine transaminase (ALT), and aspartate aminotransferase (AST) levels while significantly alleviated high-density lipoproteins. However, SIM failed to reduce AST and ALT levels. Moreover, tested compounds displayed antioxidant effects by inducing superoxide dismutase and glutathione levels. Histopathology data also displayed protective effects of 4J and 4K against HFD-induced fatty changes and hepatic damage. In addition, 4J and 4K downregulated transcript levels of HMGCR, APOB, PCSK9, and VCAM1, and molecular docking analysis also supported the experimental data. CONCLUSION: It is conceivable from this study that 4J and 4K exert their antihyperlipidemic effects by modulating multiple targets regulating lipid levels.

Anti-Inflammatory, analgesic and anti-pyretic activity of Fagonia bruguieri DC in rats.

Traditional medicine has employed the plant Fagonia bruguieri DC. to alleviate inflammation, fever and pain. The goal of this study was to test the anti-inflammatory, analgesic and antipyretic properties of the methanol extract of whole plant of Fagonia bruguieri (F. bruguieri). The writhing test and Eddy's hot plate test were used to assess the analgesic potential of F. bruguieri at three different doses. Carrageenan-induced rat paw edema was applied to investigate anti-inflammatory activity, whereas antipyretic activity was estimated in Brewer's yeast induced pyrexia model. Flavonoids, alkaloids, saponins, tannins and glycosides were found in F. bruguieri's phytochemical analysis. F. bruguieri at 750 mg/kg reduced writhing count by 62.23 percent, while F. bruguieri enhanced latency in Eddy's hot plate test. In carrageenan-induced edema, F. bruguieri at 750 mg/kg exhibited considerable anti-inflammatory effect (41.11 percent) after 2 nd, 3 rd and 4 th hours of therapy. F. bruguieri was also found to show antipyretic properties. The anti-inflammatory, analgesic and antipyretic properties of F. bruguieri were confirmed in this study, which might be attributable to the presence of several phyto-constituents.

Aqueous Ethanolic Extract of Adiantum incisum Forssk. Protects against Type 2 Diabetes Mellitus via Attenuation of α-Amylase and Oxidative Stress.

Purpose : This study was designed to investigate the antidiabetic effects of the aqueous ethanolic extract of Adiantum incisum Forssk. whole plant (AE-AI) in order to validate the folkloric claim. Methods : Streptozotocin (STZ) was used to induce type 2 diabetes mellitus (TII DM) in male Sprague-Dawley rats. STZ-induced diabetic rats were later treated orally with either AE-AI (125, 250, and 500 mg/kg) or glibenclamide for 35 days. Blood glucose levels were measured weekly and on day 35, animals were sacrificed, and blood samples and tissues were harvested for subsequent antioxidant and histopathological analyses. AE-AI was also analyzed in vitro for phytochemical, antioxidant, and α-amylase inhibitory assays. Results : The phytochemical screening of AE-AI confirmed the presence of essential bioactive compounds like cardiac glycosides, flavonoids, phenolic compounds, saponins, and fixed oils. AE-AI demonstrated abundant amounts of total phenolic and flavonoid contents and displayed prominent antioxidant activity as assessed via DPPH, phosphomolybdate, and nitric oxide scavenging assays. AE-AI treatment also showed α-amylase inhibitory activity comparable to acarbose. In addition, AE-AI treatment exhibited a wide margin of safety in rats and dose-dependently reduced STZ-induced blood glucose levels. Moreover, AE-AI increased the levels of GSH, SOD, catalase, and reduced MDA, and therefore prevented pathological effects of STZ on the kidney, liver, and pancreas. The blood glucose regulatory effect and antioxidant activity of AE-AI also aided in normalizing TII DM-mediated dyslipidemias. GC-MS analysis also demonstrated several potential antidiabetic phytoconstituents in AE-AI. Conclusion : These findings reveal that AE-AI possesses certain pharmacologically active compounds that can effectively treat STZ-induced TII DM owing to its antioxidant and α-amylase inhibitory potentials.

ISG15 deficiency features a complex cellular phenotype that responds to treatment with itaconate and derivatives.

BACKGROUND: Congenital ISG15 deficiency is a rare autoinflammatory disorder that is driven by chronically elevated systemic interferon levels and predominantly affects central nervous system and skin. METHODS AND RESULTS: We have developed induced pluripotent stem cell-derived macrophages and endothelial cells as a model to study the cellular phenotype of ISG15 deficiency and identify novel treatments. ISG15-/- macrophages exhibited the expected hyperinflammatory responses, but normal phagocytic function. In addition, they displayed a multifaceted pathological phenotype featuring increased apoptosis/pyroptosis, oxidative stress, glycolysis, and acylcarnitine levels, but decreased glutamine uptake, BCAT1 expression, branched chain amino acid catabolism, oxidative phosphorylation, ß-oxidation, and NAD(P)H-dependent oxidoreductase activity. Furthermore, expression of genes involved in mitochondrial biogenesis and respiratory chain complexes II-V was diminished in ISG15-/- cells. Defective mitochondrial respiration was restored by transduction with wild-type ISG15, but only partially by a conjugation-deficient variant, suggesting that some ISG15 functions in mitochondrial respiration require ISGylation to cellular targets. Treatment with itaconate, dimethyl-itaconate, 4-octyl-itaconate, and the JAK1/2 inhibitor ruxolitinib ameliorated increased inflammation, propensity for cell death, and oxidative stress. Furthermore, the treatments greatly improved mitochondria-related gene expression, BCAT1 levels, redox balance, and intracellular and extracellular ATP levels. However, efficacy differed among the compounds according to read-out and cell type, suggesting that their effects on cellular targets are not identical. Indeed, only itaconates increased expression of anti-oxidant genes NFE2L2, HMOX1, and GPX7, and dimethyl-itaconate improved redox balance the most. Even though itaconate treatments normalized the elevated expression of interferon-stimulated genes, ISG15-/- macrophages maintained their reduced susceptibility to influenza virus infection. CONCLUSIONS: These findings expand the cellular phenotype of human ISG15 deficiency and reveal the importance of ISG15 for regulating oxidative stress, branched chain amino acid metabolism, and mitochondrial function in humans. The results validate ruxolitinib as treatment for ISG15 deficiency and suggest itaconate-based medications as additional therapeutics for this rare disorder.

Boswellic Acids, Pentacyclic Triterpenes, Attenuate Oxidative Stress, and Bladder Tissue Damage in Cyclophosphamide-Induced Cystitis.

Boswellic acids, derived from the Boswellia serrata plant, have been demonstrated to have anti-inflammatory properties in experimental animal models. The present study was aimed to evaluate the uro-protective effect of boswellic acids in rats with cyclophosphamide-induced cystitis. Interstitial cystitis was induced by cyclophosphamide (CYP). In order to analyze the reduction of the urothelial damage, the bladder weight, the nociception response, and the Evans blue dye extravasation from the bladder were evaluated. To investigate the involvement of lipid peroxidation and enzymatic antioxidants CAT, SOD, and GPX and MPO and NO were evaluated. IL-6 and TNF-α were measured by the ELISA immunoassay technique. The results showed that pretreatment with boswellic acids significantly reduced urothelial damage which was accompanied by a decrease in the activity of MDA, CPO, and NO levels and prevention of the depletion of CAT, SOD, and GPX. The levels of IL-6 and TNF-α were dramatically reduced by boswellic acids. Histopathological findings revealed a considerable reduction in cellular infiltration, edema, epithelial denudation, and bleeding. Our findings showed that boswellic acids, by their antioxidant and anti-inflammatory properties, negate the detrimental effects of cyclophosphamide on the bladder, suggesting boswellic acids as promising therapeutic alternatives for cystitis.

Novel acetamide derivatives of 2-aminobenzimidazole prevent inflammatory arthritis in rats via suppression of pro-inflammatory mediators.

Benzimidazole ring system is an important pharmacophore with diverse pharmacological activities. In this study, we explored the anti-arthritic effects of newly synthesized acetamide derivatives of 2-aminobenzimidazole (N1 and N2) in rats. FTIR and NMR spectroscopies were used to characterize these compounds. Carrageenan (CRG) induced paw edema model was used to test the acute anti-inflammatory activity of various doses (10, 20 and 30 mg/kg) of N1 and N2 compounds. Based on acute anti-inflammatory effects, the most potent dose of each compound was selected and investigated in complete freund's adjuvant (CFA) induced inflammatory arthritis (RA) model (n = 4 in each group). Histopathological, hematological, radiographic, and RT-qPCR analyses were performed to assess the progression or resolution of inflammatory arthritis. The tested compounds produced a dose-dependent anti-inflammatory activity against CRG induced paw inflammation and similarly reduced edema in CFA induced inflammatory arthritis model. Histopathological and X-ray analyses of ankle joints revealed minimal inflammation and normal joint structures in N1 and N2 treated groups. The tested compounds also reduced the levels of autoantibodies and restored hematological parameters. Interestingly, the tested compounds did not elevate aspartate aminotransferase and alanine transaminase levels and displayed a better safety profile than methotrexate. N1 and N2 compounds also attenuated the transcript levels of IRAK1, NF-kB1, TNF-α, IL-1ß, IL17 and MMP1. In addition, N1 displayed a greater inhibition of mRNA levels of COX1, COX2, mPGES1 and PTGDS as compared to N2. Our findings demonstrate that N1 and N2 compounds possess strong anti-arthritic activity which can be attributed to the suppression of pro-inflammatory mediators.

Pharmacological evaluation of anti-arthritic potential of terpinen-4-ol using in vitro and in vivo assays.

Terpinen 4-ol, a phytochemical is a monoterpene which has been reported for its anti-inflammatory effect. Present research was planned to check its effect against arthritis through in vitro and in vivo models. Terpinen 4-ol was evaluated through in-vitro procedures including blocking of protein (BSA and egg albumin) denaturation and human RBC membrane stabilization. In in vivo study, terpinen 4-ol (15, 30 and 60 mg/kg) was evaluated using formaldehyde and CFA arthritic models. Terpinen 4-ol significantly inhibited increase in paw and joint swelling as compared to diseased group. Terpinen 4-ol showed remarkable antioxidant effect (SOD, reducing power) and also improved body weight, haematological, histopathological and radiological parameters in CFA model. Also, moreover, the excess production of IL-1ß, TNF-α, IRAK, and NF-kB were noticeably attenuated in all terpinen 4-ol treated rats, however, IL-17 and IL-10 were distinctly increased compared to arthritic control rats in RT-PCR. Also, terpinen 4-ol showed promising antioxidant effect in DPPH assay. Henceforth, it might be concluded that terpinen 4-ol has anti-arthritic effect which can be attributed to the downregulation of pro-inflammatory cytokines.

Congenital deficiency reveals critical role of ISG15 in skin homeostasis.

Ulcerating skin lesions are manifestations of human ISG15 deficiency, a type I interferonopathy. However, chronic inflammation may not be their exclusive cause. We describe two siblings with recurrent skin ulcers that healed with scar formation upon corticosteroid treatment. Both had a homozygous nonsense mutation in the ISG15 gene, leading to unstable ISG15 protein lacking the functional domain. We characterized ISG15-/- dermal fibroblasts, HaCaT keratinocytes, and human induced pluripotent stem cell-derived vascular endothelial cells. ISG15-deficient cells exhibited the expected hyperinflammatory phenotype, but also dysregulated expression of molecules critical for connective tissue and epidermis integrity, including reduced collagens and adhesion molecules, but increased matrix metalloproteinases. ISG15-/- fibroblasts exhibited elevated ROS levels and reduced ROS scavenger expression. As opposed to hyperinflammation, defective collagen and integrin synthesis was not rescued by conjugation-deficient ISG15. Cell migration was retarded in ISG15-/- fibroblasts and HaCaT keratinocytes, but normalized under ruxolitinib treatment. Desmosome density was reduced in an ISG15-/- 3D epidermis model. Additionally, there were loose architecture and reduced collagen and desmoglein expression, which could be reversed by treatment with ruxolitinib/doxycycline/TGF-ß1. These results reveal critical roles of ISG15 in maintaining cell migration and epidermis and connective tissue homeostasis, whereby the latter likely requires its conjugation to yet unidentified targets.

Foreign direct investment, financial development, energy consumption, and air quality: A way for carbon neutrality in China.

Air quality is a social, economical, and health issue for fast-developing countries such as China. Due to the overuse of nonrenewable energy, industrialization, and the population put pressure on air quality, which seriously threatens public health and economic growth. This study focuses on air quality and also aims to investigate the short-and long-run correlation between foreign direct investment, energy consumption, domestic credit, and financial development. The Autoregressive distributed lag model and the Granger non-causality test were carried out over the period from 1985 to 2018. The main findings of this study show a positive and significant long-run impact of energy consumption on air quality. In addition, domestic credit and financial development similarly show a significant positive short-run association with air quality. Moreover, the unidirectional causality correlation running from foreign direct investment and domestic credit to air quality was concluded by the Granger non-causality test. Considering the empirical analysis, this study suggests that domestic financial institutions should offer credit to industries at a low-interest rate in order to help them to switch from non-renewable to renewable energy consumption towards the promotion of sustainable and healthy air quality.

Assessing the impact of trade openness on CO2 emissions: Evidence from China-Japan-ROK FTA countries.

After signing the Regional Comprehensive Economic Partnership trade agreement, China became a proposed signatory to another important trilateral free-trade agreement - the China-Japan-South Korea Free Trade Agreement. In the context of the agreement, we explore the potential effect and internal influencing mechanism of trade openness on this region's carbon emissions from 1970 to 2019. We further detect the impact of the agreement by splitting the full sample into two subsamples, one subperiod before the agreement was signed and the other after it was signed. Then we separately analyze the impacts of imports and exports on carbon emissions and find that: (i) Trade openness positively affects the greenhouse effect, and the signing of the agreement can reduce the promotion effect of trade openness on carbon emissions; (ii) imports contribute to increased carbon emissions while exports significantly reduce carbon emissions in a country; and (iii) expanding trade openness not only directly affects carbon emissions directly, but also has indirect impacts by affecting three main effects (i.e., scale effect, technical effect, and structure effect). Finally, several important policy suggestions are provided to mitigate the greenhouse effect and promote high-quality trade openness.

Foreign direct investment and education as determinants of environmental quality: The importance of post Paris Agreement (COP21).

This study investigates the effect of foreign direct investment and education on environmental quality for Asian countries by controlling income, energy consumption, and urbanization for the period of 1990-2018. We have applied panel cointegration techniques to probe for long-run associations among the variables. The empirical results indicate the existence of cointegration between the variables. Dynamic ordinary least square and fully modified least square methods are applied to estimate long-run elasticities. The empirical results confirm that environmental quality is sensitive to foreign direct investment, education, and urbanization. Income and energy consumption deteriorate environmental quality by increasing CO2 emissions. In the long-run, bidirectional causal associations are found for emissions- foreign direct investment, emissions-energy use, income- emissions, foreign direct investment -income, and energy-income nexus. Furthermore, there is a unidirectional causality running from education and urbanization to emissions, foreign direct investment, income, and energy use. Policymakers in Asian economies are encouraged to establish policies that increase the education budget, promote the use of green energy, attract foreign direct investment with green technology, and expand cities to limit the urbanization effects on environmental quality.