Induction Of Mediators Research Articles

Assessment of the Expression Levels of USP27X and DDX3X genes in Systemic Lupus Erythematosus (SLE) Patients

Introduction: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease influencing numerus tissues in body. Ubiquitin carboxyl-terminal hydrolase 27 (USP27X) is a deubiquitinating enzyme involved in the type I interferons (IFNs) generation, apoptosis and production of proinflammatory mediators. DEAD-box helicase 3 X-linked (DDX3X) is a ribonucleic acid (RNA) helicases and contributes to the generation of type I IFNs, and proinflammatory mediators. Considering the involvement of IFN type I, apoptotic cell death and proinflammatory mediators in the pathogenesis of SLE, the expression levels of USP27X and DDX3X genes were assessed in SLE patients. Methods: Two groups, including SLE patients and healthy subjects, were included in the study and the expression levels of USP27X and DDX3X genes in their peripheral blood mononuclear cells (PBMC) were quantified by the real-time polymerase chain reaction (PCR). Results: The results demonstrated the expression level of DDX3X gene was 5.9-fold higher in the SLE patients compared to the healthy subjects ( P < .01). No significant difference in the expression level of USP27X gene was detected between both groups ( P > .05). Conclusion: A significant elevation in the level of DDX3X gene in SLE patients prepossess the potential involvement of DDX3X in SLE pathogenesis possibly through the induction of proinflammatory mediators. In spite of the potential involvement of USP27X in SLE through the induction of type 1 IFNs, and apoptotic cell death, our finding did not provide evidence in the contribution of USP27X in SLE pathogenesis.

Preclinical Efficacy of VTX-0811: A Humanized First-in-Class PSGL-1 mAb Targeting TAMs to Suppress Tumor Growth.

Omnipresent suppressive myeloid populations in the tumor microenvironment limit the efficacy of T-cell-directed immunotherapies, become more inhibitory after administration of T-cell checkpoint inhibitors, and are overall associated with worse survival of cancer patients. In early clinical trials, positive outcomes have been demonstrated for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. We have previously described the key role of P-selectin glycoprotein ligand-1 (PSGL-1) in maintaining an inhibitory state of tumor-associated macrophages (TAMs), most of which express high levels of PSGL-1. Here we describe a novel, first-in-class humanized high-affinity monoclonal antibody VTX-0811 that repolarizes human macrophages from an M2-suppressive phenotype towards an M1 inflammatory phenotype, similar to siRNA-mediated knockdown of PSGL-1. VTX-0811 binds to PSGL-1 of human and cynomolgus macaque origins without inhibiting PSGL-1 interaction with P- and L-Selectins or VISTA. In multi-cellular assays and in patient-derived human tumor cultures, VTX-0811 leads to the induction of pro-inflammatory mediators. RNAseq data from VTX-0811 treated ex vivo tumor cultures and M2c macrophages show similar pathways being modulated, indicating that the mechanism of action translates from isolated macrophages to tumors. A chimeric version of VTX-0811, consisting of the parental murine antibody in a human IgG4 backbone, inhibits tumor growth in a humanized mouse model of cancer. VTX-0811 is exceptionally well tolerated in NHP toxicology assessment and is heading into clinical evaluation after successful IND clearance.

Abstract Tu096: The Aryl Hydrocarbon Receptor Agonist, L-Kynurenine, Modulates Cardiac Fibroblast Activation and Antigen Presentation

Background: The Aryl Hydrocarbon Receptor (AHR) is a ubiquitously expressed transcription factor that regulates the cellular response to external stimuli through the binding of ligands including tryptophan metabolites such as L-Kynurenine (L-Kyn). Alterations in tryptophan metabolic pathways and downregulation of myocardial AHR are associated with cardiac inflammation and fibrosis in experimental heart failure (HF) induced by transverse aortic constriction (TAC). We hypothesized cardiac fibroblast (CFB) AHR and its agonism by L-Kyn prevent the pro-fibrotic and pro-inflammatory activity of CFBs in experimental HF. Methods and Results: We performed TAC or sham surgery on Ahr -/- mice and WT littermates for 4 weeks and found that Ahr-/- mice showed significantly decreased contractile function measured by echocardiography, and increased collagen deposition in left ventricular histological sections after TAC compared to WT mice. We performed bulk RNA sequencing in sorted CFB (CD31-CD45-MEFSK4+) from Ahr -/- and WT mice. Gene set enrichment analysis showed Ahr -/- CFB had increased expression in pathways for fibroblast activation, chemokine production, and immune cell recruitment. To investigate the role of L-Kyn agonism of CFB AHR in transformation and contractile function, murine CFB were treated with Transforming Growth Factor β (TGFβ) (100ng/ml) or seeded in collagen discs, in the presence or absence of L-Kyn(100ug/ml). L-Kyn attenuated TGFβ mediated induction of αSMA and collagen 1 protein expression by immunofluorescence and western blot, as well as decreased disc contraction 72h after mechanical activation and release. The role of AHR agonism by L-Kyn on the pro-inflammatory function of CFB was determined in WT CFB treated with IFNγ (100U/ml) in the presence or absence of L-Kyn. IFNγ induction of chemokines Cxcl9 and Cxcl10, as well as MHC-II surface expression were attenuated by L-Kyn, so was T cell adhesion to CFB in co-culture assays. In contrast, L-Kyn had no effect on the ability of CFB to take up and process antigens, as determined by DQ-Ovalbumin internalization quantified by flow cytometry. Conclusions: Our results demonstrate that AHR regulates activation and pro-inflammatory signatures in CFB at baseline, and that stimulation of CFB transformation and pro-inflammatory activity is dampened by agonism with L-Kyn. Current studies are aimed at investigating AHR agonism in the context of pressure overload induced HF in CFB reporter mice.

Immunomodulator-Derived Nanoparticles Induce Neuroprotection and Regulatory T Cell Action to Alleviate Parkinsonism.

Post-translational modification, mitochondrial abruptions, neuroinflammation, and α-synuclein (α-Syn) aggregation are considered as major causes of Parkinson's disease (PD) pathogenesis. The recent literature highlights neuroimmune cross talk and the negative role of immune effector T (Teff) and positive regulation by regulatory T (Treg) cells in PD treatment. Herein, a strategy to endow Treg action paves the path for development of PD treatment. Thus, we explored the neuroprotective efficiency of the immunomodulator and PP2A (protein phosphatase 2) activator, FTY720 nanoparticles in in vivo experimental PD models. Repurposing of FTY720 for PD is known due to its protective effect by reducing PD and its camouflaged role in endowing EZH2-mediated epigenetic regulation of PD. EZH2-FOXP3 interaction is necessary for the neuroprotective Treg cell activity. Therefore, we synthesized FTY720 nanoparticles to improve FTY720 protective efficacy in an in vivo PD model to explore the PP2A mediated signaling. We confirmed the formation of FTY720NPs, and the results of the behavioral and protein expression study showed the significant neuroprotective efficiency of our nanoformulations. In the exploration of neuroprotective mechanism, several lines of evidence confirmed FTY720NPs mediated induction of PP2A/EZH2/FOXP3 signaling in the induction of Treg cells effect in in vivo PD treatment. In summary, our nanoformulations have novel potential to alleviate PD by inducing PP2A-induced epigenetic regulation-mediated neuroimmunomodulation at the clinical setup.

Olprinone, a Selective Phosphodiesterase III Inhibitor, Has Protective Effects in a Septic Rat Model after Partial Hepatectomy and Primary Rat Hepatocyte.

Olprinone (OLP) is a selective inhibitor of phosphodiesterase III and is used clinically in patients with heart failure and those undergoing cardiac surgery; however, little is known about the effects of OLP on hepatoprotection. The purpose of this study aimed to determine whether OLP has protective effects in in vivo and in vitro rat models of endotoxin-induced liver injury after hepatectomy and to clarify the mechanisms of action of OLP. In the in vivo model, rats underwent 70% partial hepatectomy and lipopolysaccharide treatment (PH/LPS). OLP administration increased survival by 85.7% and decreased tumor necrosis factor-α, C-X-C motif chemokine ligand 1, and inducible nitric oxide synthase (iNOS) mRNA expression in the livers of rats treated with PH/LPS. OLP also suppressed nuclear translocation and/or DNA binding ability of nuclear factor kappa B (NF-κB). Pathological liver damage induced by PH/LPS was alleviated and neutrophil infiltration was reduced by OLP. Primary cultured rat hepatocytes treated with the pro-inflammatory cytokine interleukin-1β (IL-1β) were used as a model of in vitro liver injury. Co-treatment with OLP inhibited dose-dependently IL-1β-stimulated iNOS induction and NF-κB activation. Our results demonstrate that OLP may partially inhibit the induction of several inflammatory mediators through the suppression of NF-κB and thus prevent liver injury induced by endotoxin after liver resection.

Social transmission of inflammation in mice

The ability to detect and respond to sickness in others promotes survival. Here we show that mouse dams respond to immune challenged pups by mirroring their inflammatory response. Dams with pups subjected to immune challenge displayed a marked induction of inflammatory mediators in both the brain and the periphery, accompanied by an increase in maternal behaviors and corticosterone levels. This social transmission of inflammation did not require physical contact, and it contributed to the stress hormone response in the dams. In adult dyads, interaction with an immune challenged cagemate did not elicit robust inflammatory signaling but induced an increased responsiveness to a subsequent immune challenge. The identification of social transmission of inflammation, or inflammatory responsiveness, may open new avenues for research on social behavior, just like the description of similar phenomena such as observational fear and transmitted pain has done.

DiABZI and poly(I:C) inhibit osteoclastic bone resorption by inducing IRF7 and IFIT3.

Type I interferons (IFN-I) are pleiotropic factors endowed with multiple activities that play important roles in innate and adaptive immunity. Although many studies indicate that IFN-I inducers exert favorable effects on broad-spectrum antivirus, immunomodulation, and anti-tumor activities by inducing endogenous IFN-I and IFN-stimulated genes, their function in bone homeostasis still needs further exploration. Here, our study demonstrates 2 distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. First, IFN-I inducers suppress the genes that control osteoclast (OC) differentiation and activity in vitro. Moreover, diABZI alleviates bone loss in Ti particle-induced osteolysis and ovariectomized -induced osteoporosis in vivo by inhibiting OC differentiation and function. In addition, the inhibitory effects of IFN-I inducers on OC differentiation are not observed in macrophages derived from Ifnar1-/-mice, which indicate that the suppressive effect of IFN-I inducers on OC is IFNAR-dependent. Mechanistically, RNAi-mediated silencing of IRF7 and IFIT3 in OC precursors impairs the suppressive effect of the IFN-I inducers on OC differentiation. Taken together, these results demonstrate that IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-I signaling pathway.

The Use of High-Dose Intravenous L-Ascorbate in Pain Therapy: Current Evidence from the Literature.

Pain is the most common reason for seeking medical treatment. Despite extensive research efforts and effective analgesics modulating pain, there is still a major therapeutic gap in addressing the root causes of pain. Pain is associated with tissue damage induced by oxidative stress and induction of inflammatory mediators following high consumption of antioxidants. The role of antioxidants in general, and the administration of L-ascorbate in particular, is still controversially discussed and underestimated in the daily clinical practice. The current literature on the therapeutic effect of L-ascorbate, ascorbic acid, and vitamin C on various pain conditions was evaluated against the background of evidence-based medicine. Those articles, obtained from systematic search in PubMed, were critically assessed and rated in terms of evidence level and methodological quality by two independent experts. The primary purpose of this work was to establish specific pain therapy guidance for intravenous L-ascorbate. A PubMed search revealed 14 suitable articles comprising controlled clinical trials and meta-analyses. An additional ten publications could be identified via secondary literature. There is supporting evidence for the efficacy of ascorbate treatment in inflammatory pain conditions, in the complex regional pain syndrome, in post zoster neuralgia, in neuropathic pain, in post-operative pain conditions, and in tumor-related pain. However, the considered studies differ in the type of administration, in dosage, in duration of treatment, as well as in quality of research. Despite all study heterogeneity, it became evident that research of high scientific quality is in support of the efficacy of L-ascorbate in pain treatment. Oxidative stress is present in almost all pain conditions. Because oral administration of most magistral formulas of vitamin C does not provide biological availability, parenteral administration should be preferred and can be supported by an oral dose with high bioavailability on days without intravenous treatment. L-ascorbate should be preferred for parenteral high dosage, rather than ascorbic acid, as it does not release acid valences under physiological conditions. L-ascorbate is an effective, safe, and economically favorable integrative treatment option for various pain conditions, addressing the root cause of tissue damage and inflammatory mediator burst.

Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities.

The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory and fibrogenic cascades that ultimately result in the formation of a scar. After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses. TLRs (toll-like receptors) and NLRs (NOD-like receptors) recognize damage-associated molecular patterns (DAMPs) and transduce downstream proinflammatory signals, leading to upregulation of cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], and interleukin-6) and chemokines (such as CCL2 [CC chemokine ligand 2]) and recruitment of neutrophils, monocytes, and lymphocytes. Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways. Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells. Growth factor-mediated pathways, neurohumoral cascades, and matricellular proteins deposited in the provisional matrix stimulate fibroblast activation and proliferation and myofibroblast conversion. Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation. Scar maturation requires stimulation of endogenous signals that inhibit fibroblast activity and prevent excessive fibrosis. Moreover, in the mature scar, infarct neovessels acquire a mural cell coat that contributes to the stabilization of the microvascular network. Excessive, prolonged, or dysregulated inflammatory or fibrogenic cascades accentuate adverse remodeling and dysfunction. Moreover, inflammatory leukocytes and fibroblasts can contribute to arrhythmogenesis. Inflammatory and fibrogenic pathways may be promising therapeutic targets to attenuate heart failure progression and inhibit arrhythmia generation in patients surviving myocardial infarction.

Spreading Depolarization Induces a Transient Potentiation of Excitatory Synaptic Transmission

Spreading depolarization (SD) is a slowly propagating wave of prolonged activation followed by a period of synaptic suppression. Some prior reports have shown potentiation of synaptic transmission after recovery from synaptic suppression and noted similarities with the phenomenon of long-term potentiation (LTP). Since SD is increasingly recognized as participating in diverse neurological disorders, it is of interest to determine whether SD indeed leads to a generalized and sustained long-term strengthening of synaptic connections. We performed a characterization of SD-induced potentiation, and tested whether distinctive features of SD, including adenosine accumulation and swelling, contribute to reports of SD-induced plasticity. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the hippocampal CA1 subregion of murine brain slices, and SD elicited using focal microinjection of KCl. A single SD was sufficient to induce a consistent potentiation of slope and amplitude of fEPSPs. Both AMPA- and NMDA-receptor mediated components were enhanced. Potentiation peaked ∼20 min after SD recovery and was sustained for ∼30 min. However, fEPSP amplitude and slope decayed over an extended 2-hour recording period and was estimated to reach baseline after ∼3 h. Potentiation was saturated after a single SD and adenosine A1 receptor activation did not mask additional potentiation. Induction of LTP with theta-burst stimulation was not altered by prior induction of SD and molecular mediators known to block LTP induction did not block SD-induced potentiation. Together, these results indicate an intermediate duration potentiation that is distinct from hippocampal LTP and may have implications for circuit function for 1–2 h following SD.

Inhibition of RNase 7 by RNase inhibitor promotes inflammation and Staphylococcus aureus growth: Implications for atopic dermatitis.

The antimicrobial ribonuclease RNase 7 is abundantly expressed in the epidermis of lesional skin of atopic dermatitis (AD). Host RNase inhibitor (RI) binds to RNase 7 and blocks its ribonuclease activity. This study aimed to evaluate the impact of RNase 7-RI interactions on AD. Cultured human primary keratinocytes, with siRNA-mediated downregulation of RNase 7 and RI, were stimulated with the synthetic RNA polyinosinic-polycytidylic acid (poly I:C). Induction of proinflammatory mediators was analyzed by real-time PCR and ELISA. RI expression in AD non-lesional and lesional skin biopsies and healthy controls was analyzed by real-time PCR and immunostaining. RI protein release invivo on the AD skin surface was determined by western blot. Antimicrobial and ribonuclease assays were used to investigate the functional role of RI. RNase 7 inhibited the RNA-induced expression of proinflammatory mediators in keratinocytes. Accordingly, downregulation of RNase 7 in keratinocytes enhanced RNA-mediated induction of proinflammatory mediators, whereas downregulation of RI had the opposite effect. RI was released by damaged keratinocytes and epidermis. Invivo expression and release of RI on the skin surface were enhanced in lesional AD skin. Rinsing solution from the surface of lesional AD skin blocked the ribonuclease activity of RNase 7. The anti-Staphylococcus aureus activity of RNase 7 was abrogated by RI. Our data suggest a novel role of RI as a trigger factor of inflammation in AD by blocking the ribonuclease and antimicrobial activity of RNase 7, thereby enhancing RNA-mediated inflammation and S. aureus growth.

PM2.5 Extracts Induce INFγ-Independent Activation of CIITA, MHCII, and Increases Inflammation in Human Bronchial Epithelium.

The capacity of particulate matter (PM) to enhance and stimulate the expression of pro-inflammatory mediators has been previously demonstrated in non-antigen-presenting cells (human bronchial epithelia). Nonetheless, many proposed mechanisms for this are extrapolated from known canonical molecular pathways. This work evaluates a possible mechanism for inflammatory exacerbation after exposure to PM2.5 (from Puerto Rico) and CuSO4, using human bronchial epithelial cells (BEAS-2B) as a model. The induction of CIITA, MHCII genes, and various pro-inflammatory mediators was investigated. Among these, the phosphorylation of STAT1 Y701 was significantly induced after 4 h of PM2.5 exposure, concurrent with a slight increase in CIITA and HLA-DRα mRNA levels. INFγ mRNA levels remained low amidst exposure time, while IL-6 levels significantly increased at earlier times. IL-8 remained low, as expected from attenuation by IL-6 in the known INFγ-independent inflammation pathway. The effects of CuSO4 showed an increase in HLA-DRα expression after 8 h, an increase in STAT1 at 1 h, and RF1 at 8 h We hypothesize and show evidence that an inflammatory response due to PM2.5 extract exposure in human bronchial epithelia can be induced early via an alternate non-canonical pathway in the absence of INFγ.

Dysregulated fibrinolysis and plasmin activation promote the pathogenesis of osteoarthritis.

Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. However, the role of the fibrinolytic pathway is not well understood. Here, we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator (uPA), and the uPA receptor (uPAR), was dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression after a destabilization of the medial meniscus in a mouse model whereas genetic deficiency of plasmin activator inhibitor, or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans and induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, 3'-phosphoinositide-dependent kinase-1, AKT, and ERK signaling cascades and activated matrix metalloproteinases to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.

TRIM2 Selectively Regulates Inflammation-Driven Pathological Angiogenesis without Affecting Physiological Hypoxia-Mediated Angiogenesis.

Angiogenesis is a critical physiological response to ischemia but becomes pathological when dysregulated and driven excessively by inflammation. We recently identified a novel angiogenic role for tripartite-motif-containing protein 2 (TRIM2) whereby lentiviral shRNA-mediated TRIM2 knockdown impaired endothelial angiogenic functions in vitro. This study sought to determine whether these effects could be translated in vivo and to determine the molecular mechanisms involved. CRISPR/Cas9-generated Trim2-/- mice that underwent a periarterial collar model of inflammation-induced angiogenesis exhibited significantly less adventitial macrophage infiltration relative to wildtype (WT) littermates, concomitant with decreased mRNA expression of macrophage marker Cd68 and reduced adventitial proliferating neovessels. Mechanistically, TRIM2 knockdown in endothelial cells in vitro attenuated inflammation-driven induction of critical angiogenic mediators, including nuclear HIF-1α, and curbed the phosphorylation of downstream effector eNOS. Conversely, in a hindlimb ischemia model of hypoxia-mediated angiogenesis, there were no differences in blood flow reperfusion to the ischemic hindlimbs of Trim2-/- and WT mice despite a decrease in proliferating neovessels and arterioles. TRIM2 knockdown in vitro attenuated hypoxia-driven induction of nuclear HIF-1α but had no further downstream effects on other angiogenic proteins. Our study has implications for understanding the role of TRIM2 in the regulation of angiogenesis in both pathophysiological contexts.

Geranylgeranyl isoprenoids and hepatic Rap1a regulate basal and statin-induced expression of PCSK9

LDL-C lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin-induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin-mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small-molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin-mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post-transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9.

Hepatoprotection of a Standardized Extract of Cultured Lentinula edodes Mycelia against Liver Injury Induced by Ischemia-Reperfusion and Partial Hepatectomy.

A standardized extract of cultured Lentinula edodes mycelia (ECLM, AHCC®) has been shown to have beneficial effects on organ metabolism. ECLM has been indicated to have liver protective properties by suppressing inflammatory responses. The pathogenesis of hepatic ischemia-reperfusion injury is thought to involve the induction of inflammatory mediators. However, whether ECLM affects inflammatory mediators caused by warm hepatic ischemia-reperfusion injury and partial hepatectomy (HIRI+PH) has not been clarified. In this study, we evaluated the protective effects of ECLM against liver damage caused by HIRI+PH. Rats were fed a normal diet (HIRI+PH) or a normal diet with 2% ECLM (HIRI+PH and ECLM) for ten days, then the liver and duodenal ligament were clamped and subjected to 15 min of hepatic ischemia. After 70% hepatectomy, the inflow occlusion was released, and liver and blood samples were collected at 3, 6, and 24 h. The effect of ECLM on mortality induced by 30 min of ischemia and hepatectomy was evaluated. The results showed that ECLM attenuated pathological liver damage, including apoptosis, in the rats treated with HIRI+PH, and decreased serum aminotransferase activity; ECLM decreased mRNA levels of the inflammation-related genes inducible nitric oxide synthase and C-X-C motif chemokine ligand 1, and increased mRNA levels of interleukin 10, an anti-inflammatory cytokine; ECLM increased hepatocyte growth factor mRNA levels and Ki-67 labeled nuclei in the liver at 24 h; ECLM significantly reduced HIRI+PH-induced mortality. In conclusion, ECLM may prevent HIRI+PH-induced liver injury in part by suppressing various inflammatory responses and promoting liver regeneration.

Sulforaphane Is Protective against Warm Ischemia/Reperfusion Injury and Partial Hepatectomy in Rats.

Sulforaphane (SFN) has various beneficial effects on organ metabolism. However, whether SFN affects inflammatory mediators induced by warm hepatic ischemia/reperfusion injury (HIRI) is unclear. To investigate the hepatoprotective effects of SFN using an in vivo model of HIRI and partial hepatectomy (HIRI + PH), rats were subjected to 15 min of hepatic ischemia with blood inflow occlusion, followed by 70% hepatectomy and release of the inflow occlusion. SFN (5 mg/kg) or saline was randomly injected intraperitoneally 1 and 24 h before ischemia. Alternatively, ischemia was prolonged for 30 min to evaluate the effect on mortality. The influence of SFN on the associated signaling pathways was analyzed using the interleukin 1β (IL-1β)-treated primary cultured rat hepatocytes. In the HIRI + PH-treated rats, SFN reduced serum liver enzyme activities and the frequency of pathological liver injury, such as apoptosis and neutrophil infiltration. SFN suppressed tumor necrosis factor-alpha (TNF-α) mRNA expression and inhibited nuclear factor-kappa B (NF-κB) activation by HIRI + PH. Mortality was significantly reduced by SFN. In IL-1β-treated hepatocytes, SFN suppressed the expression of inflammatory cytokines and NF-κB activation. Taken together, SFN may have hepatoprotective effects in HIRI + PH in part by inhibiting the induction of inflammatory mediators, such as TNF-α, via the suppression of NF-κB in hepatocytes.

The Wiser Strategy of Using Beta-Agonists in Asthma: Mechanisms and Rationales.

Concerns regarding the safety of beta-2 agonists have led to revisions of the major asthma guidelines to better address these issues. Although these updates allow for a combination of previous and current strategies, they may confuse clinical practitioners. Beta-2 agonists are vital for alleviating asthma symptoms by relaxing smooth muscles; however, they also pose significant risks by inducing pro-inflammatory mediators both in vitro and in vivo. In addition to the risks of overuse and symptom masking, the use of beta-agonists alone at therapeutic doses can worsen airway inflammation and enhance virus-induced inflammation during asthma exacerbation. Inhaled corticosteroids (ICS) can effectively prevent these adverse effects. With new insights into the mechanisms of these adverse events, reserving short-acting beta-agonists for acute symptom relief during exacerbations and only for those who are already on ICS or oral steroids represents a careful approach to using beta-agonists with least adverse effects in patients with asthma. However, a major drawback of this approach is the potential non-compliance with ICS, leading to beta-agonist use without the necessary counteraction by ICS. An optimal strategy, both during and outside exacerbations, would integrate beta-agonists into an anti-inflammatory regimen that includes ICS, ideally combined with the same inhaler to ensure their concurrent use where finances allow. This would maintain the beneficial effects of beta-agonists, such as bronchodilation, while preventing the adverse effects from the induction of inflammatory mediators. This method is aligned with diverse clinical settings, maximizes the safe use of beta-agonists, and supports a comprehensive guideline-compliant management strategy.

Self-induced electron attraction center formation with pyrophosphorylation strategy for photocatalytic hydrogen evolution.

An integral approach towards augmenting the performance of photocatalytic hydrogen production lies in the induction of charge transfer mediators within the material matrix itself, thereby facilitating swift and efficient charge transfer processes. Here, CoTiO3 is induced to grow its electronic attraction center, CoP3, through a high-temperature phosphatization strategy. CoP3 acts as the active reduction site for the hydrogen evolution reaction and enhances the photocatalytic performance of the pristine catalyst. Compared with pure CoTiO3, the PCTO7 hybrid catalyst with the electronic attraction center CoP3 exhibits a superior photocatalytic performance and good stability. Experimental results show that the hydrogen evolution performance of the PCTO7 hybrid catalyst reaches 56.52 μmol, which is 78 times higher than that of the single catalyst CoTiO3 (0.72 μmol). These results demonstrate that the hybrid catalyst with the self-induced electronic attraction center has a higher light absorption capacity, faster charge carrier dynamics and improved photogenerated charge carrier separation and transfer than pure CoTiO3, resulting in excellent redox capability. DFT calculations provide evidence supporting the topological metal properties of CoP3 as the electron sink center. This study provides a feasible approach for enhancing the photocatalytic performance of a pristine catalyst employing a high-temperature phosphatization-induced electron sink center.

The influence of silver nanoparticles on the process of epithelial transition in the context of cancer metastases.

Exposure to nanoparticles (NPs) can occur in a variety of occupational situations. Ultrafine particles of natural and anthropological origin toxicity has been described in epidemiological studies. Meanwhile, the risks associated with NPs exposure are not comprehensively assessed. A wide spectrum of NPs toxicity has been demonstrated, mainly through the induction of oxidative stress and inflammatory mediators. Among the newly described mechanisms of NPs toxicity is the induction of fibrosis via the epithelial-mesenchymal transition (EMT), which is also a key mechanism of cancer metastasis. The effect of NPs on EMT in the context of metastasis has not been sufficiently described so far, and the results of studies do not allow for the formulation of unambiguous conclusions. Therefore, the aim of the work was to determine the biological activity of silver NPs against MDA-MB-436 triple-negative breast cancer cells. Exposure to nanoparticles (NPs) can occur in a variety of occupational situations. Ultrafine particles of natural and anthropological origin toxicity has been described in epidemiological studies. Meanwhile, the risks associated with NPs exposure are not comprehensively assessed. A wide spectrum of NPs toxicity has been demonstrated, mainly through the induction of oxidative stress and inflammatory mediators. Among the newly described mechanisms of NPs toxicity is the induction of fibrosis via the epithelial-mesenchymal transition (EMT), which is also a key mechanism of cancer metastasis. The effect of NPs on EMT in the context of metastasis has not been sufficiently described so far, and the results of studies do not allow for the formulation of unambiguous conclusions. Therefore, the aim of the work was to determine the biological activity of silver NPs against MDA-MB-436 triple-negative breast cancer cells. Silver nanoparticles (AgNPs) cause a statistically significant increase in relative expression of all tested mesenchymal EMT markers - cadherin 2, vimentin, matrix metalloproteinase 2 and matrix metalloproteinase 9. At the same time, reduction of epithelial cadherin 1 expression was observed. The level of MDA-MB-436 migration and TGF-beta 1 secretion was slighty increased in AgNPs-treated cells, with no influence on invasion potential. Potentially prometastatic effect of AgNPs encourages further work on the safety of nanomaterials. Med Pr Work Health Saf. 2023;74(6):541-8.