Effect of Coenzyme Q10 Supplementation on Vascular Endothelial Function: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Coenzyme Q10 (CoQ10) has gained attention as a potential therapeutic agent for improving endothelial function. Several randomized clinical trials have investigated CoQ10 supplementation's effect on endothelial function. However, these studies have yielded conflicting results, therefore this systematic review and meta-analysis were conducted. AIM: This systematic review and meta-analysis were conducted to assess the effects of CoQ10 supplementation on endothelial factors. METHODS: A comprehensive search was done in numerous databases until July 19th, 2023. Quantitative data synthesis was performed using a random-effects model, with weight mean difference (WMD) and 95% confidence intervals (CI). Standard methods were used for the assessment of heterogeneity, meta-regression, sensitivity analysis, and publication bias. RESULTS: 12 studies comprising 489 subjects were included in the meta-analysis. The results demonstrated significant increases in Flow Mediated Dilation (FMD) after CoQ10 supplementation (WMD: 1.45; 95% CI: 0.55 to 2.36; p < 0.02), but there is no increase in Vascular cell adhesion protein (VCAM), and Intercellular adhesion molecule (ICAM) following Q10 supplementation (VCAM: SMD: - 0.34; 95% CI: - 0.74 to - 0.06; p < 0.10) (ICAM: SMD: - 0.18; 95% CI: - 0.82 to 0.46; p < 0.57). The sensitivity analysis showed that the effect size was robust in FMD and VCAM. In meta-regression, changes in FMD percent were associated with the dose of supplementation (slope: 0.01; 95% CI: 0.004 to 0.03; p = 0.006). CONCLUSIONS: CoQ10 supplementation has a positive effect on FMD in a dose-dependent manner. Our findings show that CoQ10 has an effect on FMD after 8 weeks of consumption. Additional research is warranted to establish the relationship between CoQ10 supplementation and endothelial function.

Actinidia arguta Extract Containing Myo-Inositol Suppresses TNF-α-Induced VCAM-1 Expression and Monocyte Adhesion to Endothelial Cells via Inhibition of the PTEN/Akt/GSK-3ß and NF-κB Signaling Pathways.

The primary inflammatory process in atherosclerosis, a major contributor to cardiovascular disease, begins with monocyte adhering to vascular endothelial cells. Actinidia arguta (kiwiberry) is an edible fruit that contains various bioactive components. While A. arguta extract (AAE) has been recognized for its anti-inflammatory characteristics, its specific inhibitory effect on early atherogenic events has not been clarified. We used tumor necrosis factor-α (TNF-α)-stimulated human umbilical vein endothelial cells (HUVECs) for an in vitro model. AAE effectively hindered the attachment of THP-1 monocytes and reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) in HUVECs. Transcriptome analysis revealed that AAE treatment upregulated phosphatase and tensin homolog (PTEN), subsequently inhibiting phosphorylation of AKT and glycogen synthase kinase 3ß (GSK3ß) in HUVECs. AAE further hindered phosphorylation of AKT downstream of the nuclear factor kappa B (NF-κB) signaling pathway, leading to suppression of target gene expression. Oral administration of AAE suppressed TNF-α-stimulated VCAM-1 expression, monocyte-derived macrophage infiltration, and proinflammatory cytokine expression in C57BL/6 mouse aortas. Myo-inositol, identified as the major compound in AAE, played a key role in suppressing THP-1 monocyte adhesion in HUVECs. These findings suggest that AAE could serve as a nutraceutical for preventing atherosclerosis by inhibiting its initial pathogenesis.

Saponins from Allium macrostemon Bulbs Attenuate Endothelial Inflammation and Acute Lung Injury via the NF-κB/VCAM-1 Pathway.

Endothelial inflammation is a multifaceted physiological process that plays a pivotal role in the pathogenesis and progression of diverse diseases, encompassing but not limited to acute lung infections like COVID-19, coronary artery disease, stroke, sepsis, metabolic syndrome, certain malignancies, and even psychiatric disorders such as depression. This inflammatory response is characterized by augmented expression of adhesion molecules and secretion of pro-inflammatory cytokines. In this study, we discovered that saponins from Allium macrostemon bulbs (SAMB) effectively inhibited inflammation in human umbilical vein endothelial cells induced by the exogenous inflammatory mediator lipopolysaccharide or the endogenous inflammatory mediator tumor necrosis factor-α, as evidenced by a significant reduction in the expression of pro-inflammatory factors and vascular cell adhesion molecule-1 (VCAM-1) with decreased monocyte adhesion. By employing the NF-κB inhibitor BAY-117082, we demonstrated that the inhibitory effect of SAMB on VCAM-1 expression may be attributed to the NF-κB pathway's inactivation, as characterized by the suppressed IκBα degradation and NF-κB p65 phosphorylation. Subsequently, we employed a murine model of lipopolysaccharide-induced septic acute lung injury to substantiate the potential of SAMB in ameliorating endothelial inflammation and acute lung injury in vivo. These findings provide novel insight into potential preventive and therapeutic strategies for the clinical management of diseases associated with endothelial inflammation.

Muscone inhibits the progression of atherosclerotic plaques in mice aorta by inhibiting the NF-κB/p65 pathway.

Atherosclerosis (AS) is considered to be one of the main pathogenic factors of coronary heart disease, cerebral infarction and peripheral vascular disease. Oxidative stress and inflammation run through the occurrence and development of atherosclerosis and related cardiovascular events. Muscone is a natural extract of deer musk and also the main physiological active substance of musk. This study investigated the impact of muscone on atherosclerosis. ApoE-/- mice were used to establised AS model and injected with low-dose (4 mg/kg/day) or high-dose (8 mg/kg/day) of muscone intraperitoneally for 4 weeks. Then aortic tissues were collected, and pathological sections of the aorta were prepared for oil red staining, HE and masson staining. The changes of MDA, SOD, VCAM-1, NF-κB, and TNF-α were observed by Western blotting or immunofluorescence staining. The results showed that high-dose muscone could effectively reduce the plaque area/aortic root area and relative atherosclerotic area, reduce the collagen composition in plaque tissue. In addition, we also found that high-dose muscone can effectively increase MDA level, reduce the level of SOD, and inhibit the expression of VCAM-1, NF-κB/p65, TNF-α in arterial plaques. Our results indicate that the administration of muscone has the benefit of inhibiting atherosclerosis. The potential mechanisms may be associated with antioxidant effect and inhibition of inflammatory reaction in arterial plaques. With the increasing understanding of the relationship between muscone and atherosclerosis, muscone has high potential value as a new drug to treat atherosclerosis.

Assessing Mailuoning injection in wound healing and thrombophlebitis management: A rat model study.

Thrombophlebitis is the inflammatory condition characterized by obstruction of one or more vessels, commonly in the legs, due to the formation of blood clots. It has been reported that traditional Chinese medicine, including Mailuoning injection, is advantageous for treating inflammatory and blood disorders. This research assessed the therapeutic efficacy of Mailuoning injection in the treatment of thrombophlebitis in rodents, as well as investigated its impact on fibrinolysis, inflammation, and coagulation. An experimental setup for thrombophlebitis was established in rodents via modified ligation technique. Five groups comprised the animals: sham operation group, model group, and three Mailuoning treatment groups (low, medium, and high dosages). The pain response, edema, coagulation parameters (PT, APTT, TT, FIB), serum inflammatory markers (IL-6, TNF-α, CRP), and expression levels of endothelial markers (ICAM-1, VCAM-1, NF-κB) were evaluated. Blood flow and vascular function were further assessed by measuring hemorheological parameters and the concentrations of TXB2, ET, and 6-k-PGF1α. In contrast to the sham group, model group demonstrated statistically significant increases in endothelial expression levels, coagulation latencies, and inflammatory markers (p < 0.05). The administration of mailing, specifically at high and medium dosages, resulted in a substantial reduction in inflammatory markers, enhancement of coagulation parameters, suppression of ICAM-1 and VCAM-1 expression, and restoration of hemorheological measurements to baseline (p < 0.05). Significantly higher concentrations of 6-k-PGF1α and lower levels of TXB2 and ET were observed in high-dose group, suggesting that pro- and anti-thrombotic factors were restored to equilibrium. Utilization of Mailuoning injection in rat model of thrombophlebitis exhibited significant therapeutic impact. This effect was manifested through pain alleviation, diminished inflammation, enhanced blood viscosity and facilitation of fibrinolysis. The study indicated that Mailuoning injection may serve as a viable therapeutic option for thrombophlebitis, potentially aiding in the improvement of wound healing by virtue of its anti-inflammatory and blood flow-enhancing characteristics.

[Effects of Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination on inflammatory responses in atherosclerotic mice].

The study aims to observe the effects and explore the mechanisms of Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination in the treatment of the inflammatory response of mice with atherosclerosis(AS) via the Toll-like receptor 4(TLR4)/myeloid differentiation primary response protein 88(MyD88)/nuclear factor-κB(NF-κB) signaling pathway. Male ApoE~(-/-) mice were randomly assigned into a model group, a Buyang Huanwu Decoction group, an Astragali Radix-Angelicae Sinensis Radix combination group, and an atorvastatin group, and male C57BL/6J mice of the same weeks old were used as the control group. Other groups except the control group were given high-fat diets for 12 weeks to establish the AS model, and drugs were administrated by gavage. Aortic intimal hyperplasia thickness, blood lipid level, plasma inflammatory cytokine levels, M1/M2 macrophage markers, and expression levels of proteins in TLR4/MyD88/NF-κB pathway in the vessel wall were measured to evaluate the effects of drugs on AS lesions and inflammatory responses. The results showed that the AS model was successfully established with the ApoE~(-/-) mice fed with high-fat diets. Compared with the control group, the model group showed elevated plasma total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c) levels(P<0.05), thickened intima(P<0.01), and increased plasma tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) levels(P<0.01). Moreover, the model group showed increased expression of vascular cell adhesion molecule-1(VCAM-1) and inducible nitric oxide synthase(iNOS)(P<0.01), inhibited expression of endothelial nitric oxide synthase(eNOS) and cluster of differentiation 206(CD206)(P<0.01), and up-regulated mRNA and protein levels of TLR4, MyD88, NF-κB inhibitor alpha(IκBα), and NF-κB in the vessel wall(P<0.05). Compared with the model group, Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination lowered the plasma TC and LDL-c levels(P<0.01), alleviated the intimal hyperplasia(P<0.01), and reduced the plasma TNF-α and IL-6 levels(P<0.05). Moreover, the two interventions promoted the expression of eNOS and CD206(P<0.05), inhibited the expression of VCAM-1 and iNOS(P<0.01), and down-regulated the mRNA and protein levels of TLR4, MyD88, IκBα, and NF-κB(P<0.05) in the vessel wall. This study indicated that Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination could delay the progression of AS, inhibit the polarization of vascular wall macrophages toward M1 type, and attenuate vascular inflammatory response by inhibiting the activation of TLR4/MyD88/NF-κB signaling pathway in the vascular wall. Astragali Radix and Angelicae Sinensis Radix were the main pharmacological substances in Buyang Huanwu Decoction for alleviating the AS vascular inflammatory response.

[Effect of Isodon ternifolius-medicated serum on hepatic stellate cells based on TLR4/NF-κB/NLRP3 signaling pathway].

The present study aimed to investigate the inhibitory effect and mechanism of Isodon terricolous-medicated serum on lipopolysaccharide(LPS)-induced hepatic stellate cell(HSC) activation. LPS-induced HSCs were divided into a blank control group, an LPS model group, a colchicine-medicated serum group, an LPS + blank serum group, an I. terricolous-medicated serum group, a Toll-like receptor 4(TLR4) blocker group, and a TLR4 blocker + I. terricolous-medicated serum group. HSC proliferation was detected by methyl thiazolyl tetrazolium(MTT) assay. Enzyme-linked immunosorbent assay(ELISA) was used to measure type Ⅰ collagen(COL Ⅰ), COL Ⅲ, transforming growth factor-ß1(TGF-ß1), intercellular adhesion molecule-1(ICAM-1), α-smooth muscle actin(α-SMA), vascular cell adhesion molecule-1(VCAM-1), cysteinyl aspartate-specific proteinase-1(caspase-1), and monocyte chemotactic protein-1(MCP-1). Real-time PCR(RT-PCR) was used to detect mRNA expression of TLR4, IκBα, and NOD-like receptor thermal protein domain associated protein 3(NLRP3), nuclear factor-κB(NF-κB) p65, gasdermin D(GSDMD), and apoptosis-associated speck-like protein containing a CARD(ASC) in HSCs. Western blot(WB) was used to detect the protein levels of TLR4, p-IκBα, NF-κB p65, NLRP3, ASC, and GSDMD in HSCs. The results showed that I. terricolous-medicated serum could inhibit the proliferation activity of HSCs and inhibit the secretion of COL Ⅰ, COL Ⅲ, α-SMA, TGF-ß1, caspase-1, MCP-1, VCAM-1, and ICAM-1 in HSCs. Compared with the LPS model group, the I. terricolous-medicated serum group, the colchicine-medicated serum group, and the TLR4 blocker group showed down-regulated expression of p-IκBα, NLRP3, NF-κB p65, GSDMD, and ASC, and up-regulated expression of IκBα. Compared with the TLR4 blocker group, the TLR4 blocker + I. terricolous-medicated serum group showed decreased expression of TLR4, p-IκBα, NLRP3, NF-κB p65, GSDMD, and ASC, and increased expression of IκBα. In conclusion, I. terricolous-medicated serum down-regulates HSC activation by inhibiting the TLR4/NF-κB/NLRP3 signaling pathway.

In Vitro Anti-Inflammatory and Vasculoprotective Effects of Red Cell Extract from the Black Sea Urchin Arbacia lixula.

Sea urchins have emerged as an important source of bioactive compounds with anti-inflammatory and antioxidant properties relevant to human health. Since inflammation is a crucial pathogenic process in the development and progression of atherosclerosis, we here assessed the potential anti-inflammatory and vasculoprotective effects of coelomic red-cell methanolic extract of the black sea urchin Arbacia lixula in an in vitro model of endothelial cell dysfunction. Human microvascular endothelial cells (HMEC-1) were pretreated with A. lixula red-cell extract (10 and 100 µg/mL) before exposure to the pro-inflammatory cytokine tumor necrosis factor (TNF)-α. The extract was non-toxic after 24 h cell treatment and was characterized by antioxidant power and phenol content. The TNF-α-stimulated expression of adhesion molecules (VCAM-1, ICAM-1) and cytokines/chemokines (MCP-1, CCL-5, IL-6, IL-8, M-CSF) was significantly attenuated by A. lixula red-cell extract. This was functionally accompanied by a reduction in monocyte adhesion and chemotaxis towards activated endothelial cells. At the molecular level, the tested extract significantly counteracted the TNF-α-stimulated activation of the pro-inflammatory transcription factor NF-κB. These results provide evidence of potential anti-atherosclerotic properties of A. lixula red-cell extract, and open avenues in the discovery and development of dietary supplements and/or drugs for the prevention or treatment of cardiovascular diseases.

Ginkgolide C attenuates cerebral ischemia/reperfusion-induced inflammatory impairments by suppressing CD40/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. (Ginkgoaceae), a traditional Chinese medicine, has been applied for thousands of years for the treatment of cardio-cerebral vascular diseases in China. It is written in Compendium of Materia Medica that Ginkgo has the property of "dispersing poison", which is now referred to as anti-inflammatory and antioxidant. Ginkgolides are important active ingredients in Ginkgo biloba leaves and ginkgolide injection has been frequently applied in clinical practice for the treatment of ischemic stroke. However, few studies have explored the effect and mechanism of ginkgolide C (GC) with anti-inflammatory activity in cerebral ischemia/reperfusion injury (CI/RI). AIM OF THE STUDY: The present study aimed to demonstrate whether GC was capable of attenuating CI/RI. Furthermore, the anti-inflammatory effect of GC in CI/RI was explored around the CD40/NF-κB pathway. MATERIALS AND METHODS: In vivo, middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in rats. The neuroprotective effect of GC was assessed by neurological scores, cerebral infarct rate, microvessel ultrastructure, blood-brain barrier (BBB) integrity, brain edema, neutrophil infiltration, and levels of TNF-α, IL-1ß, IL-6, ICAM-1, VCAM-1, and iNOS. In vitro, rat brain microvessel endothelial cells (rBMECs) were preincubated in GC before hypoxia/reoxygenation (H/R) culture. The cell viability, levels of CD40, ICAM-1, MMP-9, TNF-α, IL-1ß, and IL-6, and activation of NF-κB pathway were examined. In addition, the anti-inflammatory effect of GC was also investigated by silencing CD40 gene in rBMECs. RESULTS: GC attenuated CI/RI as demonstrated by decreasing neurological scores, reducing cerebral infarct rate, improving microvessel ultrastructural features, ameliorating BBB disruption, attenuating brain edema, inhibiting MPO activity, and downregulating levels of TNF-α, IL-1ß, IL-6, ICAM-1, VCAM-1, and iNOS. Coherently, in rBMECs exposed to H/R GC enhanced cell viability and downregulated levels of ICAM-1, MMP-9, TNF-α, IL-1ß, and IL-6. Furthermore, GC suppressed CD40 overexpression and hindered translocation of NF-κB p65 from the cytosol to the nucleus, phosphorylation of IκB-α, and activation of IKK-ß in H/R rBMECs. However, GC failed to protect rBMECs from H/R-induced inflammatory impairments and suppress activation of NF-κB pathway when CD40 gene was silenced. CONCLUSIONS: GC attenuates cerebral ischemia/reperfusion-induced inflammatory impairments by suppressing CD40/NF-κB pathway, which may provide an available therapeutic drug for CI/RI.

Molecular imaging of liver inflammation using an anti-VCAM-1 nanobody.

To date, a biopsy is mandatory to evaluate parenchymal inflammation in the liver. Here, we evaluated whether molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) could be used as an alternative non-invasive tool to detect liver inflammation in the setting of chronic liver disease. To do so, we radiolabeled anti-VCAM-1 nanobody (99mTc-cAbVCAM1-5) and used single-photon emission computed tomography (SPECT) to quantify liver uptake in preclinical models of non-alcoholic fatty liver disease (NAFLD) with various degree of liver inflammation: wild-type mice fed a normal or high-fat diet (HFD), FOZ fed a HFD and C57BL6/J fed a choline-deficient or -supplemented HFD. 99mTc-cAbVCAM1-5 uptake strongly correlates with liver histological inflammatory score and with molecular inflammatory markers. The diagnostic power to detect any degree of liver inflammation is excellent (AUROC 0.85-0.99). These data build the rationale to investigate 99mTc-cAbVCAM1-5 imaging to detect liver inflammation in patients with NAFLD, a largely unmet medical need.

A multi-target protective effect of Danggui-Shaoyao-San on the vascular endothelium of atherosclerotic mice.

BACKGROUND: Atherosclerosis (AS) is a chronic disease characterized by abnormal blood lipid metabolism, inflammation and vascular endothelial injury. Vascular endothelial injury is the initial stage during the occurrence of AS. However, the function and mechanism of anti-AS are not well characterized. Danggui-Shaoyao-San (DGSY) is a classic Traditional Chinese Medicine (TCM) prescription for the treatment of gynecological diseases, and has been widely used in the treatment of AS in recent years. METHODS: ApoE-/- atherosclerosis male mice were established by feeding with high-fat diet, and then randomly divided into three groups: Atherosclerosis group (AS), Danggui-Shaoyao-San group (DGSY), and Atorvastatin calcium group (X). The mice were administered with the drugs for 16 weeks. Pathological changes in aortic vessels were examined by staining with Oil red O, Masson and hematoxylin-eosin. In addition, blood lipids were analyzed. The level of IL-6 and IL-8 in aortic vessels were detected by ELISA and the expression of ICAM-1 and VCAM-1 in the aortic vascular endothelium were measured by Immunohistochemical. The mRNA expression of interα5ß1/c-Abl/YAP in the aortic vessels were measured by Real-time quantitative PCR and location of expression was assessed by immunofluorescence. RESULTS: DGSY can significantly reduce the content of TC,TG and LDL-C and increase the level of HDL-C in the serum, reduce the plaque area and inhibit the concentration of IL-6 and IL-8, down-regulate the expression of IVAM-1,VCAM-1 and interα5ß1/ c-Abl/YAP in the aortic vessels. CONCLUSIONS: Collectively, DGSY can alleviate vascular endothelium damage and delay the occurrence of AS, and the underlying mechanism may be related to the multi-target protective of DGSY.

Chinese herbal formula, modified Xianfang Huoming Yin, alleviates the inflammatory proliferation of rat synoviocytes induced by IL-1ß through regulating the migration and differentiation of T lymphocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Xianfang Huoming Yin (XFH) is a traditional Chinese herbal formula, which has the effect of clearing heat and detoxifying toxins, dispersing swellings, activating blood circulation, and relieving pain. It is usually applied to treat various autoimmune diseases, including Rheumatoid arthritis (RA). AIM OF THE STUDY: The migration of T lymphocytes plays an indispensable role in the pathogenesis of RA. Our previous studies demonstrated that modified Xianfang Huoming Yin (XFHM) could modulate the differentiation of T, B, and NK cells, and contribute to the restoration of immunologic balance. It also could downregulate the production of pro-inflammatory cytokines by regulating the activation of NF-κ B and JAK/STAT signaling pathways in the collagen-induced arthritis mouse model. In this study, we want to investigate whether XFHM has therapeutic effects on the inflammatory proliferation of rat fibroblast-like synovial cells (FLSs) by interfering with the migration of T lymphocytes in vitro experiments. MATERIALS AND METHODS: High performance liquid chromatography-electrospray ionization/mass spectrometer system was used to identify the constituents of the XFHM formula. A co-culture system of rat fibroblast-like synovial cells (RSC-364 cells) and peripheral blood lymphocytes stimulated by interleukin-1 beta (IL-1ß) was used as the cell model. IL-1ß inhibitor (IL-1ßRA) was used as a positive control medicine, and two concentrations (100 µg/mL and 250 µg/mL) of freeze-dried XFHM powder were used as intervention measure. The lymphocyte migration levels were analyzed by the Real-time xCELLigence analysis system after 24 h and 48 h of treatment. The percentage of CD3+CD4+ T cells and CD3+CD8+ T cells, and the apoptosis rate of FLSs were detected by flow cytometry. The morphology of RSC-364 cells was observed by hematoxylin-eosin staining. The protein expression of key factors for T cell differentiation and NF-κ B signaling pathway-related proteins in RSC-364 cells were examined by western-blot analysis. The migration-related cytokines levels of P-selectin, VCAM-1, and ICAM-1 in the supernatant were measured by enzyme-linked immunosorbent assay. RESULTS: Twenty-one different components in XFHM were identified. The migration CI index of T cells was significantly decreased in treatment with XFHM. XFHM also could significantly downregulate the levels r of CD3+CD4+T cells and CD3+CD8+T cells that migrated to the FLSs layer. Further study found that XFHM suppresses the production of P-selectin, VCAM-1, and ICAM-1. Meanwhile, it downregulated the protein levels of T-bet, ROR γ t, IKKα/ß, TRAF2, and NF-κ B p50, upregulated the expression of GATA-3 and alleviated synovial cells inflammation proliferation, contributing to the FLSs apoptosis. CONCLUSION: XFHM could attenuate the inflammation of synovium by inhibiting T lymphocyte cell migration, regulating differentiation of T cells through modulating the activation of the NF-κ B signaling pathway.

Protective effects of omega-3 fatty acids in a blood-brain barrier-on-chip model and on postoperative delirium-like behaviour in mice.

BACKGROUND: Peripheral surgical trauma can trigger neuroinflammation and ensuing neurological complications, such as delirium. The mechanisms whereby surgery contributes to postoperative neuroinflammation remain unclear and without effective therapies. Here, we developed a microfluidic-assisted blood-brain barrier (BBB) device and tested the effects of omega-3 fatty acids on neuroimmune interactions after orthopaedic surgery. METHODS: A microfluidic-assisted BBB device was established using primary human cells. Tight junction proteins, vascular cell adhesion molecule 1 (VCAM-1), BBB permeability, and astrocytic networks were assessed after stimulation with interleukin (IL)-1ß and in the presence or absence of a clinically available omega-3 fatty acid emulsion (Omegaven®; Fresenius Kabi, Bad Homburg, Germany). Mice were treated 1 h before orthopaedic surgery with 10 µl g-1 body weight of omega-3 fatty acid emulsion i.v. or equal volumes of saline. Changes in pericytes, perivascular macrophages, BBB opening, microglial activation, and inattention were evaluated. RESULTS: Omega-3 fatty acids protected barrier permeability, endothelial tight junctions, and VCAM-1 after exposure to IL-1ß in the BBB model. In vivo studies confirmed that omega-3 fatty acid treatment inhibited surgery-induced BBB impairment, microglial activation, and delirium-like behaviour. We identified a novel role for pericyte loss and perivascular macrophage activation in mice after surgery, which were rescued by prophylaxis with i.v. omega-3 fatty acids. CONCLUSIONS: We present a new approach to study neuroimmune interactions relevant to perioperative recovery using a microphysiological BBB platform. Changes in barrier function, including dysregulation of pericytes and perivascular macrophages, provide new targets to reduce postoperative delirium.

Redox imbalance in COVID-19 pathophysiology.

BACKGROUND: The pathophysiologic significance of redox imbalance is unquestionable as numerous reports and topic reviews indicate alterations in redox parameters during corona virus disease 2019 (COVID-19). However, a more comprehensive understanding of redox-related parameters in the context of COVID-19-mediated inflammation and pathophysiology is required. METHODS: COVID-19 subjects (n = 64) and control subjects (n = 19) were enrolled, and blood was drawn within 72 h of diagnosis. Serum multiplex assays and peripheral blood mRNA sequencing was performed. Oxidant/free radical (electron paramagnetic resonance (EPR) spectroscopy, nitrite-nitrate assay) and antioxidant (ferrous reducing ability of serum assay and high-performance liquid chromatography) were performed. Multivariate analyses were performed to evaluate potential of indicated parameters to predict clinical outcome. RESULTS: Significantly greater levels of multiple inflammatory and vascular markers were quantified in the subjects admitted to the ICU compared to non-ICU subjects. Gene set enrichment analyses indicated significant enhancement of oxidant related pathways and biochemical assays confirmed a significant increase in free radical production and uric acid reduction in COVID-19 subjects. Multivariate analyses confirmed a positive association between serum levels of VCAM-1, ICAM-1 and a negative association between the abundance of one electron oxidants (detected by ascorbate radical formation) and mortality in COVID subjects while IL-17c and TSLP levels predicted need for intensive care in COVID-19 subjects. CONCLUSION: Herein we demonstrate a significant redox imbalance during COVID-19 infection affirming the potential for manipulation of oxidative stress pathways as a new therapeutic strategy COVID-19. However, further work is requisite for detailed identification of oxidants (O2•-, H2O2 and/or circulating transition metals such as Fe or Cu) contributing to this imbalance to avoid the repetition of failures using non-specific antioxidant supplementation.

Capsanthin from Capsicum annum fruits exerts anti-glaucoma, antioxidant, anti-inflammatory activity, and corneal pro-inflammatory cytokine gene expression in a benzalkonium chloride-induced rat dry eye model.

Dry eye disease (DED) is a complex ocular surface inflammatory disease. Its occurrence varies widely over the world, ranging from 5% to 34%. The use of preservatives, specifically benzalkonium chloride, in the ocular drops worsens the DED conditions. Furthermore, the Covid-19 pandemic increased screen time and the use of face masks and shields. As a result, the number of people suffering from dry eye disease (DED) has increased significantly in recent years. The main objective of our study is to find a solution to manage the dry eye disease (DED) preferably from natural source without any adverse events. In this study, the beneficial effects of capsanthin from Capsicum annum (CCA) were evaluated on benzalkonium chloride (BAC)-induced dry eye disease (DED) in Albino Wistar rats. Oral supplementation of CCA resulted in a statistically significant decrease in intraocular pressure (IOP) (p < .0001), increase in tear break-up time (TBUT) (p < .01), decline in Schirmer test results (p < .01), and decrease in corneal surface inflammation (p < .01). Capsanthin ameliorated in reducing oxidative stress by increasing serum antioxidant levels such as glutathione peroxidase (GPX), nitric oxide (NO), and lactoferrin (LTF) and inhibiting matrix metalloproteinases 2 and 9 (MMP2 and MMP9) (p < .0001). Capsanthin treatment significantly inhibited the expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interleukins (IL-2, IL-4, IL-6), and pro-inflammatory mediator, matrix metalloproteinase-9 (MMP9). Furthermore, the lacrimal gland expressed vascular cell adhesion molecule (VCAM-1), and prostaglandin-endoperoxide synthase 2 (PTGS2) was suppressed by CCA treatment. PRACTICAL APPLICATIONS: Benzalkonium chloride (BAC), a preservative widely used in the topical ocular drug delivery system (ODDS), causes undesirable effects such as dry eye disease as well as ameliorating intraocular pressure leading to optical nerve damage and irreversible vision loss. Capsanthin from Capsicum annum (CCA) can be used to treat symptoms related to dry eye disease such as inflammation, eye irritation, visual disturbance, ocular discomfort with potential damage to the ocular surface. The CCA may be beneficial in the treatment of glaucoma, an elevated intraocular pressure. Capsanthin from C. annum can be useful in managing DED by increasing tear break-up time (TBUT), declining in Schirmer test results and decreasing in corneal surface inflammation.

The role of solar and geomagnetic activity in endothelial activation and inflammation in the NAS cohort.

This study investigated the associations between solar and geomagnetic activity and circulating biomarkers of systemic inflammation and endothelial activation in the Normative Aging Study (NAS) cohort. Mixed effects models with moving day averages from day 0 to day 28 were used to study the associations between solar activity (sunspot number (SSN), interplanetary magnetic field (IMF)), geomagnetic activity (planetary K index (Kp index), and various inflammatory and endothelial markers. Biomarkers included intracellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), C-reactive protein (CRP), and fibrinogen. After adjusting for demographic and meteorological variables, we observed significant positive associations between sICAM-1 and sVCAM-1 concentrations and solar and geomagnetic activity parameters: IMF, SSN, and Kp. Additionally, a negative association was observed between fibrinogen and Kp index and a positive association was observed for CRP and SSN. These results demonstrate that solar and geomagnetic activity might be upregulating endothelial activation and inflammation.

Wenyang Huazhuo Tongluo formula alleviates pulmonary vascular injury and downregulates HIF-1α in bleomycin-induced systemic sclerosis mouse model.

BACKGROUND: Vascular damage, autoimmune abnormalities, and fibrosis are the three pathological features of systemic sclerosis (SSc).However, pulmonary vascular damage is the main factor affecting the progression and prognosis of SSc. The main purpose of this study was to explore the molecular mechanism of Wenyang Huazhuo Tongluo Formula in alleviating pulmonary vascular injury in bleomycin-induced SSc mouse model. METHODS: Masson staining and H&E staining were used to analyze the degree of pulmonary vascular fibrosis and the infiltration of leukocyte cells in lung tissue ofbleomycin-induced SSc mouse models treated with saline (BLM group), Wenyang Huazhuo Tongluo Formula (WYHZTL group) and HIF-1α inhibitor KC7F2 (KC7F2 group). Blood vessel exudation was determined by analyzing the cell number and albumin concentration in bronchoalveolar lavage fluid using a cell counter and ELISA assay, respectively. The degree of vascular injury was assessed by measuring the expression levels of vWF, E-selectin, ICAM-1, VCAM-1, VE-cadherin and claudin-5 in serum and pulmonary vascular endothelial cells using ELISA and immunofluorescence staining. Finally, the effect of Wenyang Huazhuo Tongluo Formula on the expression of HIF-1α was detected using immunofluorescence staining. RESULTS: Wenyang Huazhuo Tongluo Formula and KC7F2 significantly inhibited bleomycin-induced pulmonary vascular fibrosis and the level of perivascular inflammatory cell infiltration. The number of cells and the concentration of albumin were significantly reduced in the bronchoalveolar lavage fluid of the WYHZTL group and KC7F2 group compared with the BLM group. In addition, treatment with Wenyang Huazhuo Tongluo Formula and KC7F2 significantly downregulated the expression levels of vWF, E-selectin, ICAM-1, VCAM-1 and HIF-1α, but upregulated the expression of VE-cadherin and claudin-5 in serum and pulmonary vascular endothelial cells, compared with treatment with saline. CONCLUSIONS: This study reveals that Wenyang Huazhuo Tongluo Formula plays a new role in the treatment of SSc by alleviating pulmonary vascular damage. Furthermore, we found that Wenyang Huazhuo Tongluo Formula alleviates pulmonary vascular injury and inhibits HIF-1α expression.

Gynura procumbens (Lour.) Merr. extract attenuates monocyte adherence to endothelial cells through suppression of the NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Gynura procumbens (Lour.) Merr. (GP) is a herbaceous plant that grows in Malaysia and other parts of Southeast Asia. The herb is consumed as a remedy for various inflammatory-associated diseases, such as cancer, rheumatism, hypertension, diabetes mellitus and hyperlipidemia. Scientific studies demonstrate that GP extract possesses cardioprotective and anti-inflammatory effects. Cardiovascular disease is mainly caused by atherosclerosis, and inflammation plays a major role in all phases of atherosclerosis. The early inflammatory events in atherogenesis are the activation of endothelial cells and the recruitment of monocytes. AIM OF THE STUDY: This study aimed to evaluate the inhibitory effect of 80% ethanol extract of GP leaves (GPE) on the adherence of monocytes to the activated human endothelial cells and its underlying mechanism. MATERIAL AND METHODS: Qualitative and quantitative analyses of the extract were carried out by using a validated HPLC and UHPLC-MS/MS methods. The MTT test was used to select the range of concentration of extract for this study. The effect of GPE on TNF-α-induced monocyte-endothelial interaction was determined by the in vitro adhesion assay. Expression of cell surface proteins (ICAM-1, VCAM-1) and phosphorylation of nuclear factor kappa B (NF-κB) were determined by western blot, while expression of a chemokine (MCP-1) was identified by an enzyme-linked immunosorbent assay. RESULTS: HPLC and UHPLC-MS/MS analyses indicated that GPE contained chlorogenic acid, nicotiflorin and astragalin as the major compounds. GPE at 20, 40 and 60 µg/mL concentrations showed a significant reduction in monocyte adherence to endothelial cells and expression of ICAM-1 and MCP-1. However, only GPE at concentrations of 40 and 60 µg/mL was able to reduce VCAM-1 expression. Furthermore, GPE significantly inhibited IKKα/ß, IκBα, NF-κB phosphorylation and NF-κB translocation. CONCLUSION: In conclusion, GPE may inhibit monocyte adherence to the activated endothelial cells and expression of ICAM-1, VCAM-1 and MCP-1, which are important proteins for monocyte-endothelial interaction, by suppressing the NF-κB signaling pathway. The results of this study support the traditional use of GPE to counteract inflammation-associated diseases and suggest that GP can be a potential source for bioactive compounds for the development of anti-inflammatory agents to prevent atherosclerosis.

Tanshinone IIA-Loaded Micelles Functionalized with Rosmarinic Acid: A Novel Synergistic Anti-Inflammatory Strategy for Treatment of Atherosclerosis.

Rosmarinic acid (RA) and tanshinone IIA (TA) which are effective components in Salvia miltiorrhiza show anti-inflammatory potential against atherosclerosis. Based on polysulfated propylene-polyethylene glycol (PPS-PEG), RA was grafted onto this polymer via amide bonds to form a micelle carrier for TA encapsulation: PPS-PEG-RA@TA. A potent inhibitory effect on lipopolysaccharide (LPS) -induced proliferation of endothelial cells with significant intracellular uptake was observed with this system. This could have been the result of release of TA in a reactive oxygen species (ROS) environment and stronger antioxidant effect of RA. The synergistic effect was optimized when the combination was used in a molar ratio of 1:1. Mechanistic studies showed that, compared with PPS-PEG-RA and TA+RA, PPS-PEG-RA@TA micelles could more effectively regulate the nuclear factor-kappa B (NF-κB) pathway to reduce expression of vascular cell adhesion molecule-1 (VCAM-1), inhibit the inflammatory cascade and reduce endothelial-cell injury. One month after intravenous injection of PPS-PEG-RA@TA micelles, the plaque area in murine aortic vessels was reduced significantly, and serious toxic side-effects were not observed in vivo, along with excellent biocompatibility. In summary, PPS-PEG-RA@TA micelles could achieve synergistic treatment of atherosclerosis.

Cardio-protective and Anti-atherosclerosis Effect of Crocetin on Vitamin D3 and HFD-induced Atherosclerosis in Rats.

Cardiovascular disease (CVD) is a chronic disease and causes the highest rate of death globally. CVD-related deaths account for 80% of all deaths in low and middle-income countries, such as China. Crocetin (CT), a carotenoid phytoconstituent already confirm their anti-inflammatory and antioxidant effects in various diseases animal models. In the study, we make effort to access the cardio-protective effect of Crocetin against vitamin D3 and high fat induced atherosclerosis in rats and scrutinize the underlying mechanism. Sprague Dawley (SD) rats were used in this study and rats were divided into different groups and high fat diet and vitamin D was used for induction the atherosclerosis. The rats were received oral administration of crocetin (5, 10 and 15 mg/kg) and simvastatin (0.5 mg/kg) until 30 days. At the end of the experimental period, lipid, cardiac markers, anti-inflammatory, antioxidant, pro-inflammatory cytokines and atherogenic index were estimated. The mRNA expression of Intercellular adhesion molecule-1 (ICAM-1), Monocyte Chemoattractant Protein-1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1) in aortic tissue of the atherosclerotic rats. Crocetin significantly reduced the aortic membrane thickness and platelet aggregation rates. Crocetin also dose-dependently reduced total cholesterol (TC), very low-density lipoprotein (VLDL), triacylglycerol (TG), low-density lipoprotein (LDL) and augmented the level of high-density lipoprotein (HDL) level. Additionally, Crocetin significantly (p < 0.001) abridged the level of malonaldehyde (MDA) and augmented the level of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione peroxidase (GPx). Furthermore, Crocetin significantly (p < 0.001) dose-dependently reduced the levels of pro-inflammatory cytokines and inflammatory mediators. Crocetin attenuated mRNA expression of VCAM-1, ICAM-1 and MCP-1. Crocetin had anti-atherosclerosis and cardio-protective effects on vitamin D3 and high fat induced atherosclerosis in rats through anti-inflammatory and antioxidant mechanisms.