Showing papers on "Heme oxygenase published in 2023"
TL;DR: In this article, the authors found that each 3-fold increment in acrolein metabolites was cross-sectionally associated with 5.91-6.52% decrement in homeostasis model assessment-insulin sensitivity (HOMA-IS) and 0.07-0.96% of these associations.
Abstract: Acrolein is an identified high-priority hazardous air pollutant ubiquitous in daily life and associated with cardiometabolic risk that attracts worldwide attention. However, the etiology role of acrolein exposure in glucose dyshomeostasis and type 2 diabetes (T2D) is unclear. This repeated-measurement prospective cohort study included 3522 urban adults. Urine/blood samples were repeatedly collected for determinations of acrolein metabolites (N-acetyl-S-(3-hydroxypropyl)-l-cysteine, N-acetyl-S-(2-carboxyethyl)-l-cysteine; acrolein exposure biomarkers), glucose homeostasis, and T2D at baseline and a three-year follow-up. We found that each 3-fold increment in acrolein metabolites was cross-sectionally associated with 5.91-6.52% decrement in homeostasis model assessment-insulin sensitivity (HOMA-IS) and 0.07-0.14 mmol/L, 4.02-4.57, 5.91-6.52, 19-20, 18-19, and 23-31% increments in fasting glucose (FPG), fasting insulin (FPI), HOMA-insulin resistance (HOMA-IR), risks of prevalent IR, impaired fasting glucose (IFG), and T2D, respectively; longitudinally, participants with sustained-high acrolein metabolite levels had increased risks of incident IR, IFG, and T2D by 63-80, 87-99, and 120-154%, respectively (P < 0.05). In addition, biomarkers of heme oxygenase-1 activity (exhaled carbon monoxide), lipid peroxidation (8-iso-prostaglandin-F2α), protein carbonylation (protein carbonyls), and oxidative DNA damage (8-hydroxy-deoxyguanosine) mediated 5.00-38.96% of these associations. Our study revealed that acrolein exposure may impair glucose homeostasis and increase T2D risk via mediating mechanisms of heme oxygenase-1 activation, lipid peroxidation, protein carbonylation, and oxidative DNA damage.
4 citations
TL;DR: In this article , the effects of increasing concentrations of carnosine on cell viability were investigated, showing that at a concentration of 20 mM, it led to a decrease of cell viability, paralleled by gene expression increase and decrease, respectively, of interleukin 6 and heme oxygenase 1.
Abstract: The activity of microglia is fundamental for the regulation of numerous physiological processes including brain development, synaptic plasticity, and neurogenesis, and its deviation from homeostasis can lead to pathological conditions, including numerous neurodegenerative disorders. Carnosine is a naturally occurring molecule with well-characterized antioxidant and anti-inflammatory activities, able to modulate the response and polarization of immune cells and ameliorate their cellular energy metabolism. The better understanding of microglia characteristics under basal physiological conditions, as well as the possible modulation of the mechanisms related to its response to environmental challenges and/or pro-inflammatory/pro-oxidant stimuli, are of utmost importance for the development of therapeutic strategies. In the present study, we assessed the activity of carnosine on human HMC3 microglial cells, first investigating the effects of increasing concentrations of carnosine on cell viability. When used at a concentration of 20 mM, carnosine led to a decrease of cell viability, paralleled by gene expression increase and decrease, respectively, of interleukin 6 and heme oxygenase 1. When using the maximal non-toxic concentration (10 mM), carnosine decreased nitric oxide bioavailability, with no changes in the intracellular levels of superoxide ion. The characterization of energy metabolism of HMC3 microglial cells under basal conditions, never reported before, demonstrated that it is mainly based on mitochondrial oxidative metabolism, paralleled by a high rate of biosynthetic reactions. The exposure of HMC3 cells to carnosine seems to ameliorate microglia energy state, as indicated by the increase in the adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio and energy charge potential. The improvement of cell energy metabolism mediated by 10 mM carnosine could represent a useful protective weapon in the case of human microglia undergoing stressing conditions.
3 citations
TL;DR: In this paper , the authors investigated the role and underlying mechanisms of HO-1 in NASH pathogenesis and found that HO is a critical defense against oxidative stress and inflammation in the liver injury.
Abstract: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) and lacks effective treatment options. Heme oxygenase‐1 (HO‐1) is a critical defense against oxidative stress and inflammation in the liver injury. This study aims to investigate the protective role and underlying mechanisms of HO‐1 in NASH pathogenesis.
3 citations
TL;DR: Li et al. as discussed by the authors used CRISPR technology to generate the HO1HEPKO mice and showed that HO1 seemed to exert deleterious effects and promote inflammation in NAFLD.
Abstract: In this issue, Li et al.1 advanced our understanding of heme oxygenase1 (HO1) in nonalcoholic fatty liver disease (NAFLD). They developed hepatocytespecific HO1 knockout (KO) mice (HO1HEPKO) and used LO2 human hepatocytes with HO1 knocked down or overexpressed. For the past decade, there has been a conundrum regarding the role of HO1 in liver diseases. Most studies show a protective action of HO1 in NAFLD.2– 4 However, in 2014, Jais et al. created hepatocytespecific HO1 knockout mice they named Lhoko and showed the opposite, that is, HO1 seemed to exert deleterious effects and promote inflammation in NAFLD.5 This work demonstrated increased HO1 mRNA expression in dietinduced fatty liver, similar to the present Li et al. study,1 which found that HO1 mRNA levels were also significantly higher with highfat feedinginduced NAFLD. However, the two studies have entirely different findings regarding the role of HO1 in NAFLD. The dichotomy in the findings could arise from how the mice were generated in each study. Li et al. utilized CRISPR technology to generate the HO1HEPKO mice,1 and Jais et al. used classical homologous recombination to insert LoxP sites flanking exon 2 of the HO1 gene locus.5 Jais et al. crossed these animals with AlbCre transgenic mice generating the Lhoko mice,5 which caused a frameshift in exon 3 and an early stop codon that resulted in a truncated peptide consisting of nine amino acids. One must wonder whether the truncated nine amino acid peptide originating from the HO1 gene in the Lhoko mice might have some protective action causing a differential finding compared to the HO1HEPKO mice described by Li et al.1 The vast majority of the scientific literature has demonstrated the protective effects of HO1 as a protector against oxidative stress and as an inhibitor of lipid accumulation with favorable effects on health and NAFLD (Figure 1). In the study by Li et al.1 they determined the effects of HO1 on mitochondria with and without treatments with palmitic acid to mimic the environment for determining the mechanism by which HO1 interacts with mitochondrial function in fatloaded hepatocytes. HO1 has been previously shown to be located in the mitochondria of the liver and controls mitochondrial heme and its metabolism to bilirubin.6 To identify the function of HO1 on mitochondria, Li et al. used mitochondrial microarray analysis in their HO1HEPKO and littermate mice,1 in which they identified that HO1 inhibits the gene translocase of outer mitochondrial membrane 20 (Tomm20). They show that the loss of hepatic HO1 in mice and human hepatocytes significantly increased Tomm20 mRNA by ~eightfold in KO compared to ~fourfold in WT. This was correlated with higher mitochondrial dysfunction with lower levels of HO1, which was indicated by increased mitochondrial fragmentation and mitochondrial fission. To support that Tomm20 induces mitochondrial dysfunction, they used shRNA to suppress levels and demonstrate that this improves mitochondria function. The effect of HO1 on mitochondrial function was further evidenced by showing that when the HO1 levels are low, it impairs mitochondrial membrane potential, decreases ATP production, enhances mitochondrial reactive oxygen species (ROS) production, and causes mitochondrial DNA damage both in vivo and in vitro. The induction of HO1 can be done via dietary supplements, which are protective against NAFLD.7 The profound effect that the induction of HO1 has in attenuating ROS production is likely due to increased levels of bilirubin generation.8 Bilirubin is one of the most potent endogenous antioxidants in the body,9 and mice lacking the biliverdin reductase A (BVRA) enzyme, which is responsible for the reduction of biliverdin to bilirubin, exhibit high levels of ROS production.10,11 Bilirubin can also impact mitochondrial function by acting as a hormone through its interaction with the nuclear receptor, PPARα.12– 15
2 citations
TL;DR: In this paper , the molecular mechanism of action of natural antioxidants on lung cancer cells has been investigated by relying on the Nrf2/HO-1 axis, which is considered a dual-edged sword with beneficial features for both normal and cancer cells by regulating the gene expression of the array of endogenous antioxidant enzymes.
Abstract: Oxidative stresses (OSs) are considered a pivotal factor in creating various pathophysiological conditions. Cells have been able to move forward by modulating numerous signaling pathways to moderate the defects of these stresses during their evolution. The company of Kelch-like ECH-associated protein 1 (Keap1) as a molecular sensing element of the oxidative and electrophilic stress and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) as a master transcriptional regulator of the antioxidant response makes a master cytoprotective antioxidant pathway known as the Keap1/Nrf2 pathway. This pathway is considered a dual-edged sword with beneficial features for both normal and cancer cells by regulating the gene expression of the array of endogenous antioxidant enzymes. Heme oxygenase-1 (HO-1), a critical enzyme in toxic heme removal, is one of the clear state indicators for the duality of this pathway. Therefore, Nrf2/HO-1 axis targeting is known as a novel strategy for cancer treatment. In this review, the molecular mechanism of action of natural antioxidants on lung cancer cells has been investigated by relying on the Nrf2/HO-1 axis.
2 citations
TL;DR: In this paper , an anticancer regimen that increases intratumoral cobalt levels through targeted nanomaterial delivery is proposed, where cobaltous oxide nanodots are loaded into dendritic mesoporous silica nanoparticles, generating a biocompatible product iCoDMSN.
Abstract: High cobalt (Co) levels in tumors are associated with good clinical prognosis. An anticancer regimen that increases intratumoral Co through targeted nanomaterial delivery is proposed in this study. Bovine serum albumin and cobalt dichloride are applied to prepare cobaltous oxide nanodots using a facile biomineralization strategy. After iRGD peptide conjugation, the nanodots are loaded into dendritic mesoporous silica nanoparticles, generating a biocompatible product iCoDMSN. This nanocomposite accumulates in tumors after intravenous injection by deep tissue penetration and can be used for photoacoustic imaging. Proteomics research and molecular biology experiments reveal that iCoDMSN is a potent ferroptosis inducer in cancer cells. Mechanistically, iCoDMSNs upregulate heme oxygenase 1 (HMOX1), which increases transferrin receptors and reduces solute carrier family 40 member 1 (SLC40A1), resulting in Fe2+ accumulation and ferroptosis initiation. Furthermore, upregulated nuclear factor erythroid 2-related factor 2 (NRF2), arising from the reduction in Kelch-like ECH-associated protein 1 (KEAP1) expression, is responsible for HMOX1 enhancement after iCoDMSN treatment. Owing to intensified ferroptosis, iCoDMSN acts as an efficient radiotherapy enhancer to eliminate cancer cells in vitro and in vivo. This study demonstrates a versatile Co-based nanomaterial that primes ferroptosis by expanding the labile iron pool in cancer cells, providing a promising tumor radiotherapy sensitizer.
2 citations
TL;DR: In this paper , the authors investigated whether HO-1 is required for normal cornification of epidermal keratinocytes, and they showed that HO is transcriptionally upregulated during the terminal differentiation of human keratinocyte in vitro and in vivo.
Abstract: The epidermal barrier of mammals is initially formed during embryonic development and continuously regenerated by the differentiation and cornification of keratinocytes in postnatal life. Cornification is associated with the breakdown of organelles and other cell components by mechanisms which are only incompletely understood. Here, we investigated whether heme oxygenase 1 (HO-1), which converts heme into biliverdin, ferrous iron and carbon monoxide, is required for normal cornification of epidermal keratinocytes. We show that HO-1 is transcriptionally upregulated during the terminal differentiation of human keratinocytes in vitro and in vivo. Immunohistochemistry demonstrated expression of HO-1 in the granular layer of the epidermis where keratinocytes undergo cornification. Next, we deleted the Hmox1 gene, which encodes HO-1, by crossing Hmox1-floxed and K14-Cre mice. The epidermis and isolated keratinocytes of the resulting Hmox1f/f K14-Cre mice lacked HO-1 expression. The genetic inactivation of HO-1 did not impair the expression of keratinocyte differentiation markers, loricrin and filaggrin. Likewise, the transglutaminase activity and formation of the stratum corneum were not altered in Hmox1f/f K14-Cre mice, suggesting that HO-1 is dispensable for epidermal cornification. The genetically modified mice generated in this study may be useful for future investigations of the potential roles of epidermal HO-1 in iron metabolism and responses to oxidative stress.
1 citations
1 citations
TL;DR: In this paper , side population cells, which have a high drug efflux capacity and hypoxic responses in the microenvironment have both provided important insights into drug resistance in multiple myeloma (MM) patients.
Abstract: Multiple myeloma (MM) is a hematopoietic malignancy for which proteasome inhibitors have become available in recent years. However, many patients develop resistance to these drugs during treatment. Therefore, it is important to elucidate the mechanisms underlying resistance acquisition by proteasome inhibitors. Side population (SP) cells, which have a high drug efflux capacity and hypoxic responses in the microenvironment have both provided important insights into drug resistance in MM; however, little is known about the characteristics of SP cells in hypoxic microenvironments.
1 citations
1 citations
25 Feb 2023
TL;DR: In this article , the effects of engeletin on cardiac structural and electrical remodeling and its underlying mechanism were explored. And the results demonstrated that engeetin alleviated ISO-induced myocardial fibrosis and dysfunction.
Abstract: Engeletin is a potent natural compound with antioxidant and anti-inflammatory properties. However, its role in cardiac remodeling remains unclear. Herein, the aim of the present study was to explore the effects of engeletin on cardiac structural and electrical remodeling and its underlying mechanism.and results: A cardiac remodeling mice model using isoproterenol (ISO)-induced myocardial fibrosis was constructed and divided into the following four groups: control group; engeletin group; ISO group; engeletin + ISO group. Our results demonstrated that engeletin alleviated ISO-induced myocardial fibrosis and dysfunction. Moreover, engeletin significantly prolonged the QT and corrected QT (QTc) intervals, effective refractory period (ERP), and action potential duration (APD), and enhanced connexin protein 43 (Cx43) and ion channel expressions, thereby decreasing ventricular fibrillation (VF) susceptibility. Additionally, dihydroethidium staining illustrated that engeletin decreased reactive oxygen species (ROS) production. Of note, engeletin also increased the levels of superoxide dismutase and glutathione and decreased the activity of malondialdehyde and L-Glutathione oxidized. Moreover, engeletin significantly increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Furthermore, in vitro administration of an Nrf2 inhibitor abolished the anti-oxidant properties of engeletin.Engeletin ameliorated cardiac structural and electrical remodeling, ion channel remodeling, and oxidative stress induced by ISO in mice, thereby reducing VF susceptibility. These effects may be attributed to the anti-oxidant properties of engeletin associated with the Nrf2/HO-1 pathway.
TL;DR: This article investigated the mechanism by which the small molecule micronutrient curcumin could decrease inflammatory response in vitro to oral bacterium heat-killed Fusobacterium nucleatum.
Abstract: BACKGROUND AND OBJECTIVE
Plaque-induced gingival inflammation (gingivitis) is ubiquitous in humans. The epithelial barrier reacts to the presence of oral bacteria and induces inflammatory cascades. The objective of this study was to investigate the mechanism by which the small molecule micronutrient curcumin could decrease inflammatory response in vitro to oral bacterium heat-killed Fusobacterium nucleatum as curcumin could be a useful compound for combatting gingivitis already consumed by humans.
METHODS
H400 oral epithelial cell line was pre-conditioned with curcumin and the production of cytokines was measured by enzyme-linked immunosorbent assay (ELISA) and translocation of transcription factors was used to monitor inflammatory responses. Haem oxygenase (HO-1) expression and molecules that HO-1 releases were evaluated for their potential to reduce the quantity of cytokine production. Immunofluorescence microscopy and Western blotting were used to evaluate changes in transcription factor and enzyme location.
RESULTS
Pre-conditioning of H400 cells with a sub-apoptotic concentration of curcumin (20 μM) attenuated secretion of Granulocyte-Macrophage - Colony-Stimulating Factor (GM-CSF) and reduced NFkB nuclear translocation. This pre-conditioning caused an increase in nuclear Nrf2; an initial drop (at 8 h) followed by an adaptive increase (at 24 h) in glutathione; and an increase in haem oxygenase (HO-1) expression. Inhibition of HO-1 by SnPPIX prevented the curcumin-induced attenuation of GM-CSF production. HO-1 catalyses the breakdown of haem to carbon monoxide, free iron and biliverdin: the HO-1/CO anti-inflammatory pathway. Elevations in carbon monoxide, achieved using carbon monoxide releasing molecule-2 (CORM2) treatment alone abrogated F. nucleatum-induced cytokine production. Biliverdin is converted to bilirubin by biliverdin reductase (BVR). This pleiotropic protein was found to increase in cell membrane expression upon curcumin treatment.
CONCLUSION
Curcumin decreased inflammatory cytokine production induced by Fusobacterium nucleatum in H400 oral epithelial cells. The mechanism of action appears to be driven by the increase of haem oxygenase and the production of carbon monoxide.
TL;DR: In the last decade, a number of HO-2 agonists and antagonists have been synthesized, and the availability of these pharmacological tools should increase the appeal of HO2 as drug target as mentioned in this paper .
Abstract: Heme oxygenase (HO-2) is an enzyme mainly involved in the physiologic turnover of heme and intracellular gas sensing, and it is very abundant in the brain, testes, kidneys and vessels. Since 1990, when HO-2 was discovered, the scientific community has underestimated the role of this protein in health and disease, as attested by the small amount of articles published and citations received. One of the reason that have contributed to the lack of interest in HO-2 was the difficulty in upregulating or inhibiting this enzyme. However, over the last 10 years, novel HO-2 agonists and antagonists have been synthesized, and the availability of these pharmacological tools should increase the appeal of HO-2 as drug target. In particular, these agonists and antagonists could help explain some controversial aspects, such as the neuroprotective versus neurotoxic roles of HO-2 in cerebrovascular diseases. Furthermore, the discovery of HO-2 genetic variants and their involvement in Parkinson’s disease, in particular in males, opens new avenues for pharmacogenetic studies in gender medicine.
TL;DR: In this paper , the therapeutic protection of PTL-phytosomes against GEN-induced nephrotoxicity in rats was evaluated by using the Parthenolide (PTL) phytosomes.
Abstract: Nephrotoxicity is a serious complication that limits the clinical use of gentamicin (GEN). Parthenolide (PTL) is a sesquiterpene lactone derived from feverfew with various therapeutic benefits. However, PTL possesses low oral bioavailability. This study aimed to evaluate the therapeutic protective effects of PTL-phytosomes against GEN-induced nephrotoxicity in rats. The PTL was prepared as phytosomes to improve the pharmacological properties with a particle size of 407.4 nm, and surface morphology showed oval particles with multiple edges. Rats were divided into six groups: control, nano-formulation plain vehicle, PTL-phytosomes (10 mg/kg), GEN (100 mg/kg), GEN + PTL-phytosomes (5 mg/kg), and GEN + PTL-phytosomes (10 mg/kg). The administration of PTL-phytosomes alleviated GEN-induced impairment in kidney functions and histopathological damage, and decreased kidney injury molecule-1 (KIM-1). The anti-oxidative effect of PTL-phytosomes was demonstrated by the reduced malondialdehyde (MDA) concentration and increased superoxide dismutase (SOD) and catalase (CAT) activities. Furthermore, PTL-phytosomes treatment significantly enhanced sirtuin 1 (Sirt-1), nuclear factor erythroid-2-related factor-2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (NQO1), and heme oxygenase-1 (HO-1). Additionally, PTL-phytosomes treatment exhibited anti-inflammatory and anti-apoptotic properties in the kidney tissue. These findings suggest that PTL-phytosomes attenuate renal dysfunction and structural damage by reducing oxidative stress, inflammation, and apoptosis in the kidney.
TL;DR: In this paper, the potential anti-inflammatory effect of phloroglucinol (Phl) in RAW264.7 murine macrophages after lipopolysaccharides (LPS) stimulation was determined.
Abstract: BACKGROUND Inflammation is closely related to the pathogenesis of chronic illnesses. Secondary metabolites of marine seaweeds are recognized as reliable sources of bioactive compounds due to their health benefits besides their nutritional value. The objective of this study was to determine the potential anti-inflammatory effect of phloroglucinol (Phl) in RAW264.7 murine macrophages after lipopolysaccharides (LPS) stimulation.METHODS MTT, nitric oxide (NO), and DCFH-DA assays were conducted to determine cell viability, NO production, and reactive oxygen species (ROS) generation respectively. Pro-inflammatory cytokines and prostaglandin E2 (PGE2) levels were measured using ELISA assay kits. Protein expression levels were determined by western blot analysis.RESULTS Phl treatment showed a promising anti-inflammatory effect by reducing NO production, secretion of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), PGE2 production, protein expression levels of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), and ROS generation in LPS-stimulated RAW264.7 murine macrophages. Phl treatment upregulated heme oxygenase-1 (HO-1) expression by inducing nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and activating AMPK. However, Zinc protoporphyrin (ZnPP), an inhibitor of HO-1, partially reversed these effects, including NO production, pro-inflammatory cytokine secretion, iNOS, COX-2 and HO-1 expression, and ROS generation.CONCLUSION Phl has potential anti-inflammatory activities by regulating HO-1/Nrf2 pathway in LPS-stimulated RAW264.7 murine macrophages.
TL;DR: In this paper , the authors provide an overview of available evidence on the clinical significance of HO-1 signaling in prostate cancer (PCa) and suggest that the beneficial effects of HO1 induction or inhibition are dependent on whether it is a normal versus malignant cell as well as the intensity (major vs. minor) of the increase in HO1 enzymatic activity.
Abstract: Heme oxygenase 1 (HO-1) is a detoxifying antioxidant microsomal enzyme that regulates inflammation, apoptosis, cell proliferation, and angiogenesis in prostate cancer (PCa). This makes HO-1 a promising target for therapeutic prevention and treatment due to its anti-inflammatory properties and ability to control redox homeostasis. Clinical evidence highlights the possible correlation between HO-1 expression and PCa growth, aggressiveness, metastasized tumors, resistance to therapy, and poor clinical outcomes. Interestingly, studies have reported anticancer benefits mediated by both HO-1 induction and inhibition in PCa models. Contrasting evidence exists on the role of HO-1 in PCa progression and possible treatment targets. Herein, we provide an overview of available evidence on the clinical significance of HO-1 signaling in PCa. It appears that the beneficial effects of HO-1 induction or inhibition are dependent on whether it is a normal versus malignant cell as well as the intensity (major vs. minor) of the increase in HO-1 enzymatic activity. The current literature evidence indicates that HO-1 has dual effects in PCa. The amount of cellular iron and reactive oxygen species (ROS) can determine the role of HO-1 in PCa. A major increase in ROS enforces HO-1 to a protective role. HO-1 overexpression may provide cryoprotection to normal cells against oxidative stress via suppressing the expression of proinflammatory genes, and thus offer therapeutic prevention. In contrast, a moderate increase in ROS can lead to the perpetrator role of HO-1, which is associated with PCa progression and metastasis. HO-1 inhibition by xenobiotics in DNA-damaged cells tilts the balance to promote apoptosis and inhibit PCa proliferation and metastasis. Overall, the totality of the evidence revealed that HO-1 may play a dual role in the therapeutic prevention and treatment of PCa.
TL;DR: In this article , the association of HO-1, heme, and hemopexin (HPX) levels with COVID-19 severity and with markers of inflammation and coagulation activation was explored.
Abstract: Heme-oxygenase 1 (HO-1) is an enzyme with well-known anti-inflammatory and antioxidant properties, whose levels have been previously associated with disease severity in the context of sterile and infectious diseases. Moreover, the heme/HO-1 pathway has been associated with prothrombotic changes in other diseases. Accordingly, the potential of modulating HO-1 levels for the treatment of COVID-19 was extensively speculated during the COVID-19 pandemic, but very few actual data were generated. The aim of our study was to explore the association of HO-1, heme, and hemopexin (HPX) levels with COVID-19 severity and with markers of inflammation and coagulation activation. The study was conducted in 30 consecutive patients with COVID-19 admitted due to hypoxemia, and 30 healthy volunteers matched by sex, age, and geographic region. HO-1 and HPX levels were measured by enzyme immunoassay (ELISA) and heme levels were measured by a colorimetric method. A comprehensive panel of coagulation and fibrinolysis activation was also used. Patients with COVID-19 presented increased levels of HO-1 when compared to controls (5741 ± 2696 vs 1953 ± 612 pg/mL, respectively, P < 0.0001), as well as a trend toward increased levels of HPX (3.724 ± 0.880 vs 3.254 ± 1.022 mg/mL, respectively; P = 0.06). In addition, HO-1 and HPX levels reduced from admission to day + 4. HO-1 levels were associated with duration of intensive care unit stay and with several markers of coagulation activation. In conclusion, modulation of HO-1 could be associated with the prothrombotic state observed in COVID-19, and HO-1 could also represent a relevant biomarker for COVID-19. New independent studies are warranted to explore and expand these findings.
TL;DR: In this paper , the authors investigated the ability of ASP8731 to modulate pathways involved in SCD pathophysiology, and found that ASP-8731 significantly reduced microvascular stasis compared to HU alone.
Abstract: In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free heme can also activate expression of antioxidant and globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene transcription. ASP8731, is a selective small molecule inhibitor of BACH1. We investigated the ability of ASP8731 to modulate pathways involved in SCD pathophysiology. In HepG2 liver cells, ASP8731 increased HMOX1 and FTH1 mRNA. In pulmonary endothelial cells, ASP8731 decreased VCAM1 mRNA in response to TNF-α and blocked a decrease in glutathione in response to hemin. Townes-SS mice were gavaged once per day for 4 weeks with ASP8731, hydroxyurea (HU) or vehicle. Both ASP8731 and HU inhibited heme-mediated microvascular stasis and in combination, ASP8731 significantly reduced microvascular stasis compared to HU alone. In Townes-SS mice, ASP8731 and HU markedly increased heme oxygenase-1 and decreased hepatic ICAM-1, NF-kB phospho-p65 protein expression in the liver, and white blood cell counts. In addition, ASP8731 increased gamma-globin expression and HbF+ cells (F-cells) as compared to vehicle-treated mice. In human erythroid differentiated CD34+ cells, ASP8731 increased HGB mRNA and increased the percentage of F-cells 2-fold in manner similar to HU. ASP8731 and HU when given together induced more HbF+ cells compared to either drug alone. In CD34+ cells from one donor that was non-responsive to HU, ASP8731 induced HbF+ cells ~2-fold. ASP8731 and HU also increased HBG and HBA, but not HBB mRNA in erythroid differentiated CD34+ cells derived from SCD patients. These data indicate that BACH1 may offer a new therapeutic target to treat SCD.
TL;DR: In this paper , the authors investigated the function of hemin in mitigating the acute hepatotoxic effect of acetaminophen (APAP) in rat offspring and found that hemin increased GSH, TAC, and the expression of HO-1, improving the histopathological picture of liver tissue.
Abstract: The widespread use of acetaminophen (APAP) in children as an over-the-counter treatment can cause acute liver failure through accidental overdose or ingestion. Therefore, the current research sought to investigate the function of hemin in mitigating the acute hepatotoxic effect of APAP in rat offspring. Thirty-two rats were assigned into four groups: control, hemin, APAP, and hemin/APAP groups. Liver enzymes were measured in serum along with oxidative stress indicators, tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), total nitrites (NOx), and caspase 3 in liver. Immunoblotting of heme oxygenase-1 (HO-1), interleukin-6 (IL-6), Janus kinase 2 (Jak2), and signal transducer and activator of transcription 3 (STAT3) was carried out. The Bax/Bcl2 mRNA expression ratio was determined. A histological study and an immunohistochemical study of phosphorylated STAT3 were also done. Hemin reduced liver enzymes, MDA, TNF-α, NOx, caspase 3, IL-1β, p-STAT3 expression, p-Jak2 expression, IL-6 expression, and Bax/Bcl2 mRNA expression ratio. In contrast, hemin increased GSH, TAC, and the expression of HO-1, improving the histopathological picture of liver tissue. Thus, hemin could ameliorate APAP-induced hepatic toxicity in rat offspring through anti-oxidant, anti-apoptotic, and anti-inflammatory actions with a possible role for the IL-6/HO-1/Jak2/STAT3 pathway.
TL;DR: Wang et al. as discussed by the authors used network pharmacology and experimental animal validation to address osteoporotic fracture (OPF) and showed that BZYQD could improve inflammation and oxidative stress during fracture repair by suppressing NF-κB and activating Nrf2/MAPK pathways.
Abstract: Osteoporotic fracture (OPF) is one of the most common skeletal diseases in an aging society. The Chinese medicine formula Buzhong Yiqi Decoction (BZYQD) is commonly used for treating OPF. However, the essential bioactive compounds and the underlying molecular mechanisms that promote fracture repair remain unclear.We used network pharmacology and experimental animal validation to address this issue. First, 147 bioactive BZYQD compounds and 32 target genes for treating OPF were screened and assessed. A BZYQD-bioactive compound-target gene-disease network was constructed using the Cytoscape software. Functional enrichment showed that the candidate target genes were enriched in oxidative stress- and inflammation-related biological processes and multiple pathways, including nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, an OPF rat model was established and treated with BZYQD.The results revealed that BZYQD ameliorated OPF characteristics, including femoral microarchitecture, biomechanical properties, and histopathological changes, in a dose-dependent manner. Results of enzyme-linked immunosorbent assay showed that BZYQD reduced the serum's pro-inflammatory cytokines [Tumor necrosis factor-alpha (TNF-α), Interleukin (IL)-1β, and IL-6] and improved oxidative stress-related factors [glutathione (GSH) and superoxide dismutase (SOD)]. BZYQD significantly decreased the protein expression of NF-κB in OPF rat femurs, suppressed NF-κB activation, and activated the nuclear factor-erythroid factor 2-related factor (Nrf2)/heme oxygenase 1 (HO-1) and p38 MAPK as well ERK pathways.Our results suggest that BZYQD could improve inflammation and oxidative stress during fracture repair by suppressing NF-κB and activating Nrf2/MAPK signaling pathways.
TL;DR: In this article , two new naphthyridine compounds, 4methoxycarbonyl-5-oxo-1,6-naphthiridine (4methox carbonyl−4−oxo−1, 6−naphTHyridine (1) and 5methioxcarbonyll−4•oxo•1,5−1−6−nphthyridine (2), were obtained from the MeOH extracts of sponge Aaptos suberitoides.
Abstract: Two new naphthyridine compounds, 4‐methoxycarbonyl‐5‐oxo‐1,6‐naphthyridine (1) and 5‐methoxycarbonyl‐4‐oxo‐1,6‐naphthyridine (2) were obtained from the MeOH extracts of sponge Aaptos suberitoides. Their structures were determined by spectroscopic methods, including HR‐ESI‐MS, 1D‐NMR (1H‐NMR, 13C‐NMR), 2D‐NMR (COSY, HSQC, HMBC). The structure of compound 1 was further confirmed via single crystal X‐ray diffraction analysis. Compound 1 was found to reduce NO production in LPS‐induced RAW 264.7 macrophages with IC50 value of 0.15 mM. In addition, it decreased the mRNA expression levels of pro‐inflammatory mediators, such as the tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX2) in LPS‐induced macrophages. It also decreased the protein expression of iNOS and COX‐2 in LPS‐induced macrophages. Mechanistic studies further revealed that compound 1 inhibited the mitogen‐activated protein kinase (MAPK), and activated the nuclear factor erythroid 2‐related factor 2/heme oxygenase‐1 (Nrf2/HO‐1) signaling pathways in LPS‐induced RAW 264.7 macrophages.
30 Mar 2023
TL;DR: In this article , a novel experimental Heme Oxygenase-1-targeted therapy for Hormone-Refractory Prostate Cancer (HORP) was proposed.
Abstract: Supplementary Figure 4 from A Novel Experimental Heme Oxygenase-1–Targeted Therapy for Hormone-Refractory Prostate Cancer
TL;DR: In this article , a co-oximeter was used to measure carboxyhemoglobin (COHb) in Tibetans and Han Chinese male residents of Xining (2,200 m; 7,218 ft), China, using a cooximeter and Tibetan (13 women, 8 men), Han Chinese (6 women, 10 men) residents of Salt Lake City, Utah (1,413 m/4,637 ft) with a finger pulse oximeter.
Abstract: Populations living at high altitude have been subjected to the selective pressure of hypoxia due to low atmospheric pressure for hundreds of generations. Adaptive genetic signals are apparent in the genomes of present-day populations, but the links to physiological changes and underlying mechanisms are not completely understood. Our recent physiological studies revealed that Tibetans residing at intermediate altitude (2200 m; 13,780 ft) have lower hemoglobin concentration ([Hb]) and elevated carbon monoxide (CO) relative to other populations resident at the same altitude. Our previous genetic studies revealed that Tibetans residing at 4200 m (13,780 ft) exhibit a haplotype (20 kilobases) encompassing the Heme Oxygenase 2 (HMOX2) gene region. Heme oxygenase 2 protein produces carbon monoxide (CO) as a byproduct of hemoglobin breakdown. We hypothesize that HMOX2 underlies the observed CO levels at high altitude. We further hypothesize that regulatory variants could be linked to elevated heme oxygenase activity and, therefore, elevated CO levels in people of Tibetan ancestry.We measured carboxyhemoglobin (COHb) in Tibetan (n = 10) and Han Chinese (n = 8) male residents of Xining (2,200 m; 7,218 ft), China, using a co-oximeter and Tibetan (13 women, 8 men) and Han Chinese (6 women, 10 men) residents of Salt Lake City, Utah (1,413 m/4,637 ft) with a finger pulse oximeter. In the Xining cohort, COHb levels were 97% higher in Tibetans (1.01 ± 0.59 %) compared to their Han Chinese counterparts (0.51 ± 0.39 %, p < 0.048). This result was replicated in Salt Lake City, where Tibetans exhibited significantly higher COHb (4.31 ± 0.48%) compared to Han Chinese (2.00 ± 0.6%, p = 0.004).We also examined localized signals of natural selection (Composite of Multiple Signals test, CMS) from 27 previously published Tibetan genomes and identified single nucleotide variants (SNVs) within the selected haplotype with potential functional impacts on heme-oxygenase expression. Eleven variants were located within the promoter region of the HMOX2 gene. These variants exhibit significant delta allele frequencies (DAF) between Tibetans and Han Chinese (DAF > 0.2, p < 0.005) and are in high linkage disequilibrium (R2 > 0.9) in both populations. Literature and in-silico prediction tools (CIS-BP, JASPAR) indicate some of these variants have a potential gain-of-function roles as transcription factor binding sites.These results suggest adaptive, regulatory variants in HMOX2 may contribute to the observed increased endogenous CO in highland Tibetans, conferring protection from the selective stresses of high-altitude hypoxia. This project is funded by NIH R01HL145470. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
TL;DR: In this article , the effects of HO-1 and its metabolites on PCV3 infection were investigated, and it was shown that HO expression decreases in PCV-infected cells and negatively regulates PCV 3 replication while reducing ROS production.
Abstract: The regulation of host protein expression by virus infection is the key to facilitating self-replication. As an important emerging pathogen of swine, clarification of the interaction between PCV3 infection and the host enables us to understand the viral life cycle and pathogenesis better. ABSTRACT Porcine circovirus type 3 (PCV3) is a newly discovered pathogen that causes porcine dermatitis and nephropathy syndrome (PDNS)-like clinical signs, multisystemic inflammation, and reproductive failure. Heme oxygenase-1 (HO-1), a stress-inducible enzyme, exerts protective functions by converting heme into carbon monoxide (CO), biliverdin (BV), and iron. However, the effects of HO-1 and its metabolites on PCV3 replication remain unknown. In this study, experiments involving specific inhibitors, lentivirus transduction, and small interfering RNA (siRNA) transfection revealed that active PCV3 infection reduced HO-1 expression and that the expression of HO-1 negatively regulated virus replication in cultured cells, depending on its enzymatic activity. Subsequently, the effects of the HO-1 metabolites (CO, BV, and iron) on PCV3 infection were investigated. The CO inducers (cobalt protoporphyrin IX [CoPP] or tricarbonyl dichloro ruthenium [II] dimer [CORM-2]) mediate PCV3 inhibition by generating CO, and this inhibition is reversed by hemoglobin (Hb; a CO scavenger). The inhibition of PCV3 replication by BV depended on BV-mediated reactive oxygen species (ROS) reduction, as N-acetyl-l-cysteine affected PCV3 replication while reducing ROS production. The reduction product of BV, bilirubin (BR), specifically promoted nitric oxide (NO) generation and further activated the cyclic GMP/protein kinase G (cGMP/PKG) pathway to attenuate PCV3 infection. Both the iron provided by FeCl3 and the iron chelated by deferoxamine (DFO) with CoPP treatment failed to affect PCV3 replication. Our data demonstrate that the HO-1-CO-cGMP/PKG, HO-1-BV-ROS, and HO-1-BV-BR-NO-cGMP/PKG pathways contribute crucially to the inhibition of PCV3 replication. These results provide important insights regarding preventing and controlling PCV3 infection. IMPORTANCE The regulation of host protein expression by virus infection is the key to facilitating self-replication. As an important emerging pathogen of swine, clarification of the interaction between PCV3 infection and the host enables us to understand the viral life cycle and pathogenesis better. Heme oxygenase-1 (HO-1) and its metabolites carbon monoxide (CO), biliverdin (BV), and iron have been demonstrated to involve a wealth of viral replications. Here, we, for the first time, demonstrated that HO-1 expression decreases in PCV3-infected cells and negatively regulates PCV3 replication and that the HO-1 metabolic products CO and BV inhibit PCV3 replication by the CO- or BV/BR/NO-dependent cGMP/PKG pathway or BV-mediated ROS reduction, but the iron (the third metabolic product) does not. Specifically, PCV3 infection maintains normal proliferation by downregulating HO-1 expression. These findings clarify the mechanism by which HO-1 modulates PCV3 replication in cells and provide important targets for preventing and controlling PCV3 infection.
03 Apr 2023
TL;DR: In this article , the effect of genetic and pharmacologic disruption of HO-1 in the growth, invasion, and migration in androgen-sensitive (MDA PCa2b and LNCaP) and androgeninsensitive (PC3) PCa cell lines was studied.
Abstract: <div>Abstract<p>Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Inflammation has been recognized as a risk factor for this disease. Heme oxygenase 1 (HO-1), the inducible isoform of the rate-limiting enzyme in heme degradation, counteracts oxidative and inflammatory damage. Here, we investigated the regulated expression of HO-1 and its functional consequences in PCa. We studied the effect of genetic and pharmacologic disruption of HO-1 in the growth, invasion, and migration in androgen-sensitive (MDA PCa2b and LNCaP) and androgen-insensitive (PC3) PCa cell lines. Our results show that HO-1 levels are markedly decreased in PC3 compared with MDA PCa2b and LNCaP. Hemin treatment increased HO-1 at both protein and mRNA levels in all cell lines and decreased cell proliferation and invasion. Furthermore, overexpression of HO-1 in PC3 resulted in markedly reduced cell proliferation and migration. Accordingly, small interfering RNA–mediated silencing of HO-1 expression in MDA PCa2b cells resulted in increased proliferation and invasion. Using reverse transcription-quantitative PCR–generated gene array, a set of inflammatory and angiogenic genes were upregulated or downregulated in response to HO-1 overexpression identifying matrix metalloprotease 9 (MMP9) as a novel downstream target of HO-1. MMP9 production and activity was downregulated by HO-1 overexpression. Furthermore, PC3 cells stably transfected with HO-1 (PC3HO-1) and controls were injected into <i>nu</i>/<i>nu</i> mice for analysis of <i>in vivo</i> tumor xenograft phenotype. Tumor growth and MMP9 expression was significantly reduced in PC3HO-1 tumors compared with control xenografts. Taken together, these results implicate HO-1 in PCa cell migration and proliferation suggesting its potential role as a therapeutic target in clinical settings. (Mol Cancer Res 2009;7(11):1745–55)</p></div>
30 Mar 2023
TL;DR: In this paper , an expression of miR-328, miR338-3p and miRR-485-5p in SMS-CTR eRMS and CW9019 aRMS (CW).
Abstract: <p>Expression of miR-328, miR-338-3p and miR-485-5p in SMS-CTR eRMS (SMS) and CW9019 aRMS (CW).</p>
03 Apr 2023
TL;DR: In this paper , the authors proposed a solution to solve the problem of plagiarism in the domain of web design: https://www.webdesign.org/sites/webdesign/
Abstract: <p>PDF file - 33K</p>
30 Mar 2023
TL;DR: In this article , an expression of miR-328, miR338-3p and miRR-485-5p in SMS-CTR eRMS and CW9019 aRMS (CW).
Abstract: <p>Expression of miR-328, miR-338-3p and miR-485-5p in SMS-CTR eRMS (SMS) and CW9019 aRMS (CW).</p>
03 Apr 2023
TL;DR: In this article , the assessment of HO-1 expression in FAP+ macrophages in LL2/OVA tumors grown in bone marrow chimeric mice was carried out in a controlled setting.
Abstract: <p>PDF file - 64K, Assessment of HO-1 expression in FAP+ macrophages in LL2/OVA tumors grown in bone marrow chimeric mice.</p>