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Chewing areca nuts is a popular hobby in the Asian region, and areca nuts are rich in polyphenols, although some alkaloids are included. In this study, we explored the antioxidant activity of areca nut polyphenols (ANP) in lipopolysaccharides (LPS)-stimulated RAW264.7 cells. The results revealed that ANP reduced the level of reactive oxygen species (ROS) in LPS-stimulated RAW264.7 cells and enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). RNA-seq analysis showed that ANP down-regulated the transcription of genes related to the cancer pathway at 160 μg/mL, and the inflammatory pathway as well as viral infection pathway at 320 μg/mL. The cellular signaling analysis further revealed that the expressions of these genes were regulated by the mitogen-activated protein kinase (MAPK) pathway, and ANP downregulated the activation of the MAPK signaling pathway stimulated by LPS. Collectively, our findings showed that ANP inhibited the MAPK pathway and activated the Nrf2/HO-1 antioxidant pathways to reduce ROS generation induced by LPS. [ABSTRACT FROM AUTHOR]

Whisker pad skin incision in infancy causes the prolongation of mechanical allodynia after re-incision in adulthood. A recent study also proposed the importance of sex differences in pain signaling in the spinal cord. However, the sex difference in re-incision-induced mechanical allodynia in the orofacial region is not fully understood. In the rats that experienced neonatal injury in the whisker pad skin, the mechanical allodynia in the whisker pad was significantly prolonged after re-incision in adulthood compared to sham injury in infancy. No significant sex differences were observed in the duration of mechanical allodynia. The duration of mechanical allodynia in male rats was shortened by intracisternal administration of minocycline. However, minocycline had no effects on the duration of mechanical allodynia in female rats. In contrast, intracisternal administration of pioglitazone markedly suppressed mechanical allodynia in female rats after re-incision. Following re-incision, the number of peroxisome proliferator-activated receptor gamma (PPARgamma)-positive cells were reduced in the trigeminal spinal subnucleus caudalis (Vc) in female rats that experienced neonatal injury. Immunohistochemical analyses revealed that PPARgamma was predominantly expressed in Vc neurons. Pioglitazone increased the number of PPARgamma-positive Vc neurons in female rats whose whisker pad skin was incised in both infancy and adulthood stages. Pioglitazone also upregulated heme oxygenase 1 and downregulated NR1 subunit in the Vc in female rats after re-incision. Together, PPARgamma signaling in Vc neurons is a female-specific pathway for whisker pad skin incision-induced mechanical allodynia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exosomes derived from mesenchymal stem cells can inhibit neuroinflammation and some damage after intracerebral hemorrhage. There are few studies on the mechanism of neuroprotective effect of exosomes derived from mesenchymal stem cells on hippocampal neurons after intracerebral hemorrhage through heme oxygenase-1. OBJECTIVE: To explore the protection and mechanism of exosomes derived from umbilical cord mesenchymal stem cells on hippocampal neurons after intracerebral hemorrhage. METHODS: (1) A mouse model of intracerebral hemorrhage was established using autologous blood infusion, and then exosomes derived from umbilical cord mesenchymal stem cells were injected into the tail vein at 8 hours after intracerebral hemorrhage. Western blot assay was used to verify the expression of heme oxygenase 1, high mobility group box B1 and Toll-like receptor 4 at 24 hours, 4 and 30 days after intracerebral hemorrhage. (2) In vitro, the mouse hippocampal neuron cell (HT22 cell) intracerebral hemorrhage model was established by hemin stimulation, and cells were pretreated with exosomes derived from umbilical cord mesenchymal stem cells for 12 hours before modeling, and then the HT22 cells were stimulated by hemin for 6 hours. Heme oxygenase 1 expression was detected by western blot assay. (3) HT22 cells were transfected with lentivirus to reduce the expression of heme oxygenase 1, and then pretreated with exosomes derived from umbilical cord mesenchymal stem cells for 12 hours, stimulated with hemin for 6 hours. The expression of heme oxygenase 1 was detected by western blot assay. RESULTS AND CONCLUSION: (1) At 24 hours, 4 and 30 days after intracerebral hemorrhage, the expression of heme oxygenase 1 in the hippocampus on the injured side was significantly increased (all P < 0.05). Compared with the sham-operated group, the protein expression levels of heme oxygenase 1, high mobility group box B1 and Toll-like receptor 4 were significantly increased in the mice of the cerebral hemorrhage group on day 4 after cerebral hemorrhage (all P < 0.05). Compared with the intracerebral hemorrhage group, the protein expression levels of heme oxygenase 1, high mobility group box B1 and Tolllike receptor 4 in the intracerebral hemorrhage + exosome group were significantly decreased (all P < 0.05). (2) In the in vitro cerebral hemorrhage model, compared with the control group, the expression of heme oxygenase 1 protein in HT22 cells was significantly increased in the hemin+PBS group. Compared with the hemin+PBS group, the heme oxygenase 1 protein expression was significantly decreased in HT22 cells in the hemin+exosome group (all P < 0.05). (3) After lentiviral transfection of HT22 cells to knock down the expression of heme oxygenase 1, there was no significant difference in the protein expression of heme oxygenase 1 between the knockdown heme oxygenase 1+hemin+PBS group and the knockdown heme oxygenase 1+hemin+exosome group. (4) The results showed that exosomes derived from umbilical cord mesenchymal stem cells had a neuroprotective effect on injured hippocampal neurons after intracerebral hemorrhage. The mechanism may be related to the regulation of high mobility group box B1 and Toll-like receptor 4-related inflammatory pathways through heme oxygenase 1. [ABSTRACT FROM AUTHOR]

However, the detailed expression mechanisms of individual genes that can be directly involved in the oxidative stress and apoptosis of RPE cells after NF- B activation by A2E+BL are still unclear. These results suggest that NF- B binds to the I HMOX1 i gene promoter region upon A2E and BL stimuli to regulate the expression of the I HMOX1 i at the transcriptional level, and that MLL1 plays an important role in this process. Photooxidation of A2E by Blue Light Regulates Heme Oxygenase 1 Expression via NF- B and Lysine Methyltransferase 2A in ARPE-19 Cells Compared to cells treated with siNS, the occupancy of RELA in the promoter region of the I HMOX1 i gene, which was increased by BL irradiation, was slightly suppressed in MLL1-depleted cells, but it was not statistically significant (Figure 4B). [Extracted from the article]

Carbon monoxide (CO), a product of organic oxidation processes, arises in vivo principally from the enzymatic reaction of heme oxygenase (HO, transcription gene named HMX1). HO/CO has been found to exert many salutary effects in multiple biological processes, including the stress response. However, whether HO/CO is involved in the regulation of the heat-stress (HS) response of Ganoderma lucidum (G. lucidum) is still poorly understood. In this paper, we reported that under heat stress, the HMX1 transcription level, HO enzyme activity, and CO content increased by 5.2-fold, 6.5-fold and 2-fold, respectively. HMX1 silenced strains showed a 12% increase in ganoderic acid (GA) content under HS as analyzed by HPLC. Furthermore, according to Western blot analysis of the protein phosphorylation levels, HMX1 attenuated the increase in phosphorylation levels of slt2, but the phosphorylation levels were prolonged over a 3 h HS time period. The chitin and glucan content in HMX1 silenced strains increased by 108% and 75%, respectively. In summary, these findings showed that the HO/CO system responds to heat stress and then regulates the HS-induced GA biosynthesis and the cell-wall integrity mediated by the Slt-MAPK phosphorylation level in G. lucidum. [ABSTRACT FROM AUTHOR]

Tauopathies such as Alzheimer's disease are characterized by the accumulation of neurotoxic aggregates of tau protein. With aging and, especially, in Alzheimer's patients, the inducible enzyme heme oxygenase 1 (HO-1) progressively increases in microglia, causing iron accumulation, neuroinflammation, and neurodegeneration. The retina is an organ that can be readily accessed and can reflect changes that occur in the brain. In this context, we evaluated how the lack of microglial HO-1, using mice that do not express HO-1 in microglia (HMO-KO), impacts retinal macro and microgliosis of aged subjects (18 months old mice) subjected to tauopathy by intrahippocampal delivery of AAV-hTauP301L (TAU). Our results show that although tauopathy, measured as anti-TAUY9 and anti-AT8 positive immunostaining, was not observed in the retina of WT-TAU or HMO-KO+TAU mice, a morphometric study of retinal microglia and macroglia showed significant retinal changes in the TAU group compared to the WT group, such as: (i) increased number of activated microglia, (ii) retraction of microglial processes, (iii) increased number of CD68+ microglia, and (iv) increased retinal area occupied by GFAP (AROA) and C3 (AROC3). This retinal inflammatory profile was reduced in HMO-KO+TAU mice. Conclusion: Reduction of microglial HO-1 could be beneficial to prevent tauopathy-induced neuroinflammation. [ABSTRACT FROM AUTHOR]

Enterovirus 71 (EV71) is the major pathogen causing fatal neurological complications of hand, foot, and mouth disease (HFMD) in young children. Currently no effective antiviral therapy is available. In the present study, we found that natural compound Berberine (BBR) displayed potent inhibitory effects on EV71 replication in various neural cells (IC50 of 2.79-4.03 µM). In a newborn mouse model of lethal EV71 infection, Berberine at 2-5mg/kg markedly reduced mortality and clinical scores. Consistently, the replication of EV71 and pathological changes were attenuated in various infected organs including brain and lung with BBR treatment. Interestingly, EV71 infection in the brain mainly localized in the peripheral zone of brainstemand largely in astrocytes. Primary culture of astrocytes from newbornmouse brain confirmed the efficient EV71 replication that wasmostly inhibited by BBR treatment at 5 µM. Further investigations revealed remarkably elevated cellular reactive oxygen species (ROS) levels that coincided with EV71 replication in primary cultured astrocytes and various cell lines. BBR largely abolished the virus-elevated ROS production and greatly diminished EV71 replication by up-regulating NFE2 like bZIP transcription factor 2 (Nrf2) via the kelch like ECH associated protein 1 (Keap)-Nrf2 axis. The nuclear localization of Nrf2 and expression of downstream antioxidant enzymes heme oxygenase 1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) were increased significantly by BBR treatment. Collectively, our findings revealed that BBR prevents lethal EV71 neurological infection via inhibiting virus replication through regulating Keap-Nrf2 axis and ROS generation in astrocytes of brainstem, thus providing a potential antiviral treatment for severe EV71 infection associated with neurological complications. [ABSTRACT FROM AUTHOR]

Catalpol is an iridoid glycoside with rich content, rich nutrition, and numerous biological activities in Rehmanniae Radix contained in classic antidepressant prescriptions in Chinese clinical medicine. Catalpol has been confirmed previously its exact antidepressant-like effect involved heme oxygenase (HO)-1, but its antidepressant molecular targets and mechanism are still unclear. Here, catalpol's antidepressant-like molecular target was diagnosed and confirmed by ZnPP intervention [the antagonist of HO-1, (10 μg/rat), intracerebroventricular] for the first time, and its molecule mechanism network was determined through HO-1 related pathway and molecules in the hippocampus. Results showed that ZnPP significantly abolished catalpol's (10 mg/kg) reversal on depressive-like behaviors of chronic unpredictable mild stress rats, abolished catalpol's up-regulation on the phosphorylation level of extracellular regulated protein kinases (ERK)1/2 and brain-derived neurotrophic factor (BDNF)'s receptor tropomyosin-related kinase B (TrkB), the nuclear expression level of nuclear factor E 2-related factor 2 (Nrf2), the levels of anti-oxidant factors (such as HO-1, SOD, GPX, GST, GSH) and BDNF, and abolished catalpol's down-regulation on the levels of peroxide and neuroinflammation factors [cyclooxygenase-2 (COX-2), induced nitrogen monoxide synthase (iNOS), nitric oxide (NO)]. Thus, HO-1 could serve as an important potential molecular target for catalpol's antidepressant-like process, and the antidepressant-like mechanism of catalpol could at least involve the activation of HO-1 triggering the up-regulation of the ERK1/2/Nrf2/HO-1 pathway-related factors to enhance the anti-oxidant defense, triggering the down-regulation of the COX-2/iNOS/NO pathway-related factors to inhibit neuroinflammation, and triggering the up-regulation of the BDNF/TrkB pathway to enhance neurotrophy. [ABSTRACT FROM AUTHOR]

Aim: Naked mole rats (NMRs) exhibit blunted hypoxic (HVR) and hypercapnic ventilatory responses (HCVR). The mechanism(s) underlying these responses are largely unknown. We hypothesized that attenuated carotid body (CB) sensitivity to hypoxia and hypercapnia contributes to the near absence of ventilatory responses to hypoxia and CO2 in NMRs. Methods: We measured ex vivo CB sensory nerve activity, phrenic nerve activity (an estimation of ventilation), and blood gases in urethane‐anesthetized NMRs and C57BL/6 mice breathing normoxic, hypoxic, or hypercapnic gases. CB morphology, carbon monoxide, and H2S levels were also determined. Results: Relative to mice, NMRs had blunted CB and HVR. Morphologically, NMRs have larger CBs, which contained more glomus cells than in mice. Furthermore, NMR glomus cells form a dispersed pattern compared to a clustered pattern in mice. Hemeoxygenase (HO)‐1 mRNA was elevated in NMR CBs, and an HO inhibitor increased CB sensitivity to hypoxia in NMRs. This increase was blocked by an H2S synthesis inhibitor, suggesting that interrupted gas messenger signaling contributes to the blunted CB responses and HVR in NMRs. Regarding hypercapnia, CB and ventilatory responses to CO2 in NMRs were larger than in mice. Carbonic anhydrase (CA)‐2 mRNA is elevated in NMR CBs, and a CA inhibitor blocked the augmented CB response to CO2 in NMRs, indicating CA activity regulates augmented CB response to CO2. Conclusions: Consistent with our hypothesis, impaired CB responses to hypoxia contribute in part to the blunted HVR in NMRs. Conversely, the HCVR and CB are more sensitive to CO2 in NMRs. [ABSTRACT FROM AUTHOR]

Patients with sickle cell disease (SCD) display priapism. Clinical studies have shown a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD. However, there are no experimental studies that show that intravascular hemolysis promotes alterations in erectile function. Therefore, we aimed to evaluate the corpus cavernosum smooth muscle relaxant function in a murine model that displays intravascular hemolysis induced by phenylhydrazine (PHZ), as well as the role of intravascular hemolysis in increasing the stress oxidative in the penis. Corpus cavernosum strips were dissected free and placed in organ baths. Acetylcholine and electrical field stimulation (EFS)‐induced corpus cavernosum relaxations in vitro were obtained. Increased corpus cavernosum relaxant responses to acetylcholine and EFS were observed in the PHZ group. Protein expression of heme oxygenase‐1 increased in the corpus cavernosum of the PHZ group, but PDE5 protein expression was not modified. Preincubation with the heme oxygenase inhibitor 1 J completely reversed the increased relaxant responses to acetylcholine and EFS in PHZ mice. Protein expression of NADPH oxidase subunit gp91phox, 3‐nitrotyrosine, and 4‐hydroxynonenal increased in the corpus cavernosum of the PHZ group, suggesting a state of oxidative stress. Basal cGMP production was lower in the PHZ group. Our results show that intravascular hemolysis promotes increased corpus cavernosum smooth muscle relaxation associated with increased HO‐1 expression, as well as increased oxidative stress associated with upregulation of gp91phox expression. Moreover, our study supports clinical studies that point to a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD. [ABSTRACT FROM AUTHOR]

Liver cancer (L.C.) is the most common cause of cancer death in the United States and the fifth most common globally. The overexpression of nuclear factor E2 related factor 2 (Nrf2) and heme oxygenase 1 (HO‐1) caused by oxidative stress has been associated with tumor growth, aggressiveness, treatment resistance, and poor prognosis. Nutraceuticals that inhibit Nrf2/HO‐1 signaling may become the most effective strategy to treat liver cancer. Phytochemicals found in fruits and vegetables, also known as nutraceuticals, tend to emerge as chemopreventive agents, with the added benefit of low toxicity and high nutritional values. This paper reviews the present scientific knowledge of the Nrf2/HO‐1 signaling as a possible target molecule for chemotherapeutic agents, its basic control mechanisms, and Nrf2/HO‐1 inducers produced from natural products that might be employed as cancer chemopreventive drugs. The growing interest in the contribution of the Nrf2/ARE/HO‐1 signaling in the development of liver cancer and the Use of nutraceuticals to treat liver cancer by targeting Nrf2/ARE/HO‐1. Practical applications: An increase in Nrf2 expression indicates that Nrf2 is the most important player in liver cancer. Cancer patients are more resistant to chemotherapy because of this erroneous Nrf2 signaling. Furthermore, an increasing body of evidence indicates that activation of the Nrf2/HO‐1 pathway results in the production of phase II detoxifying and antioxidant enzymes, which serve a defense purpose in cells. As a consequence, treating liver cancer. This master regulator may be a possibility. Nutraceuticals that reduce Nrf2/HO‐1 signaling may be the most effective strategy for preventing liver cancer. The methods of action of numerous natural substances are examined in this article. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis is a global health problem, with increasing evidence demonstrating that oxidative stress serves a pivotal role in fibrogenesis. Riboflavin is a vital nutrient in the human and animal diet, which enhances the activity of antioxidant enzymes and ameliorates oxidative stress. The present study evaluated the effect of riboflavin on liver fibrosis and the mechanisms underlying this process. Rats were subcutaneously injected with carbon tetrachloride (CCl4) dissolved in sterile olive oil twice per week to induce hepatic fibrosis. The effect of riboflavin on CCl4-induced liver fibrosis was then assessed. Blood samples and liver tissues were collected and analyzed. The liver tissue morphological changes, immunohistochemical analysis, levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in the mitochondria, and the protein expression levels of a-smooth muscle actin (a-SMA), transforming growth factor-ß1 (TGF-ß1), extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor coactivator-1a (PGC-1a) and heme oxygenase 1 (HO-1) in the liver were also analyzed. The results demonstrated that riboflavin treatment significantly decreased the levels of alanine transaminase and aspartate transaminase in the serum, increased SOD activity and modulated the MDA level in the mitochondria. Furthermore, riboflavin significantly inhibited the CCl4-induced, upregulated protein expression levels of phosphorylated (p)-ERK, p-p38, p-JNK, TGF-ß1 and a-SMA. Moreover, riboflavin significantly increased the expression of p-AMPK, PGC-1a and HO-1 in the liver tissue. These results suggested that riboflavin delays CCl4-induced hepatic fibrosis by enhancing the mitochondrial function via the AMPK/PGC-1a/HO-1 and mitogen-activated protein kinase signaling pathways. [ABSTRACT FROM AUTHOR]

Simple Summary: Wilson's disease (WD) is a rare autosomal recessive inherited disorder of copper (Cu) metabolism, which is one of the few neurogenetic diseases with a cure. Cu deposition in the heart tissue is a mechanism of cardiac involvement. Importantly, Gandouling (GDL) effectively promotes the excretion of intracellular Cu. Therefore, the purpose of this study was to evaluate the protective effects of GDL on heart injuries and the underlying mechanisms in a copper sulfate (CuSO4)-induced animal model. The results showed that the protective effect of GDL on the heart was superior to that of penicillamine. We assessed the protective effects of Gandouling (GDL) on copper sulfate (CuSO4)-induced heart injuries in Sprague–Dawley rats, which were randomly divided into the control, CuSO4, GDL + CuSO4 and penicillamine + CuSO4 groups. The rats received intragastric GDL (400 mg/kg body weight) once per day for 42 consecutive days after 56 days of CuSO4 exposure, and penicillamine was used as a positive control. The levels of plasma inflammatory cytokines (IMA, hFABP, cTn-I and BNP) were determined using the enzyme-linked immunosorbent assay. The histopathological symptoms were evaluated using hematoxylin and eosin staining and transmission electron microscopy. To determine the underlying mechanism, Western blotting was conducted for the detection of the heme oxygenase 1 (HO-1) expression. The results revealed that GDL supplementation alleviated the histopathological symptoms of the rat heart tissue, promoted Cu excretion to attenuate impairment, and significantly decreased inflammatory cytokine levels in the plasma (p < 0.01). In addition, GDL increased the HO-1 expression in the rat hepatic tissue. The protective effect of GDL on the heart was superior to that of penicillamine. Overall, these findings indicate that GDL alleviates hepatic heart injury after a Cu overaccumulation challenge, and GDL supplements can be beneficial for patients with Wilson's disease. [ABSTRACT FROM AUTHOR]

BACKGROUND: The present study aimed to investigate whether leucine (Leu) alleviates oxidative injury in bovine intestinal epithelial cells (BIECs) induced by hydrogen peroxide (H2O2), as well as the underlying molecular mechanisms. RESULTS: BIECs were treated with H2O2 (1 mmol L−1) and/or Leu (0, 0.9, 1.8 or 3.6 mmol L−1) for 2 h. Leu increased cell viability (P < 0.05) and decreased the release of lactate dehydrogenase (P < 0.05) in BIECs challenged by H2O2. Then, the cells were treated with H2O2 (1 mmol L−1) and/or Leu (1.8 mmol L−1) for 2 h. Compared with the H2O2 group, cells treated with Leu and Leu + H2O2 exhibited increased (P < 0.05) mRNA and protein expression of superoxide dismutase 2 (SOD2), catalase (CAT), glutathione peroxidase 1 (GPx1), heme oxygenase 1 (HO‐1) and nuclear factor erythroid 2‐related factor 2 (Nrf2). BIECs treatment with Leu significantly reduced (P < 0.05) apoptosis induced by H2O2. BIECs were transfected with Nrf2 small interfering RNA (siRNA) for 48 h and/or treated with H2O2 (1 mmol L−1) and/or Leu (1.8 mmol L−1) for another 2 h. Transfection with Nrf2 siRNA abrogated the protective effect of Leu against H2O2‐induced apoptosis and the mRNA and protein expression of SOD2 (P < 0.05). CONCLUSION: These results indicate that Leu promotes the relative expression of antioxidant enzymes (SOD2, CAT and GPx1) and phase II detoxification enzymes (HO‐1) by upregulating nuclear Nrf2 and activating the Nrf2 signaling pathway, thus enhancing the antioxidant capacity of cells. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

This study evaluated the potential neuroprotective effect of azithromycin (AZ) intraperitoneal injections in male C57Bl/6 (wild type, WT) and female NOD scid gamma (NSG) mice subjected to optic nerve crush (ONC) as a model for optic neuropathy. Histologically, reduced apoptosis and improved retinal ganglion cell (RGC) preservation were noted in the AZ-treated mice as shown by TUNEL staining—in the WT mice more than in the NSG mice. The increased microglial activation following ONC was reduced with the AZ treatment. In the molecular analysis of WT and NSG mice, similar trends were detected regarding apoptosis, as well as stress-related and inflammatory markers examining BCL2-associated X (Bax), heme oxygenase 1 (Ho-1), interleukin 1 beta (Il1β), superoxide dismutase 1 (Sod1), and nuclear factor-kappa B (Nfkb) levels. In the optic nerve, AZ increased the levels of expression of Sod1 and Nfkb only in the WT mice and decreased them in the NSG mice. In the retinas of the WT and NSG mice, the Bax and Ho-1 levels of expression decreased following the AZ treatment, while the Sod1 and Nfkb expression decreased only in the WT mice, and remained stable near the baseline in the NSG mice. Il1β remained at the baseline in WT mice while it decreased towards the baseline in AZ-treated NSG mice. The neuroprotective effects demonstrated by the reduced RGC apoptosis in AZ-treated WT mice retinae, and in the optic nerves as stress-related and inflammatory gene expression increase. This did not occur in the immunodeficient NSG mice. AZ modulated the inflammatory reaction and microglial activation. The lack of an effect in NSG mice supports the assumption that AZ acts by immunomodulation, which is known to play a role in ONC damage. These findings have implications for the development and repurposing of drugs to preserve RGCs after acute optic neuropathies. [ABSTRACT FROM AUTHOR]

Rutin, also called quercetin-3-rhamnosyl glucoside, is a natural flavonol glycoside present in many plants. Rutin is used to treat various diseases, such as inflammation, diabetes, and cancer. For polymeric biomaterials, triethylene glycol dimethacrylate (TEGDMA) is the most commonly used monomer and serves as a restorative resin, a dentin bonding agent and sealant, and a bone cement component. Overall, TEGDMA induces various toxic effects in macrophages, including cytotoxicity, apoptosis, and genotoxicity. The aim of this study was to investigate the protective mechanism of rutin in alleviating TEGDMA-induced toxicity in RAW264.7 macrophages. After treatment with rutin, we assessed the cell viability and apoptosis of TEGDMA-induced RAW264.7 macrophages using an methylthiazol tetrazolium (MTT) assay and Annexin V-FITC/propidium iodide assay, respectively. Subsequently, we assessed the level of genotoxicity using comet and micronucleus assays, assessed the cysteinyla aspartate specific proteinases (caspases) and antioxidant enzyme (AOE) activity using commercial kits, and evaluated the generation of reactive oxygen species (ROS) using a dichlorodihydrofluorescein diacetate (DCFH-DA) assay. We evaluated the expression of heme oxygenase (HO)-1, the expression of nuclear factor erythroid 2 related factor (Nrf-2), and phosphorylation of AMP activated protein kinase (AMPK) using the Western blot assay. The results indicated that rutin substantially reduced the level of cytotoxicity, apoptosis, and genotoxicity of TEGDMA-induced RAW264.7 macrophages. Rutin also blocked the activity of caspase-3, caspase-8, and caspase-9 in TEGDMA-stimulated RAW264.7 macrophages. In addition, it decreased TEGDMA-induced ROS generation and AOE deactivation in macrophages. Finally, we found that TEGDMA-inhibited slightly the HO-1 expression, Nrf-2 expression, and AMPK phosphorylation would be revered by rutin. In addition, the HO-1 expression, Nrf-2 expression, and AMPK phosphorylation was enhanced by rutin. These findings indicate that rutin suppresses TEGDMA-induced caspase-mediated toxic effects through ROS generation and antioxidative system deactivation through the Nrf-2/AMPK pathway. Therefore, rutin has the potential to serve as a novel antitoxicity agent for TEGDMA in RAW264.7 macrophages. [ABSTRACT FROM AUTHOR]

Background: Retinal ischemia-reperfusion (I/R) injury often results in intractable visual impairments. The survival of retinal capillary endothelial cells is crucial for the treatment of retinal I/R injury. How to protect retinal endothelia from damage is a challenging work. Withaferin A, a small molecule derived from plants, has antibacterial and anti-inflammatory effects and has been used for about millennia in traditional medicine. The present study aimed to investigate the potential protective effect of withaferin A on retinal I/R injury. Methods: The drug-likeness of withaferin A was evaluated by the SwissADME web tool. The potential protective effect of withaferin A on the I/R-induced injury of human retinal microvascular endothelial cells (HRMECs) was investigated using multiple approaches. RNA sequencing was performed and associated mechanistic signaling pathways were analyzed based on the Kyoto Encyclopedia of Genes and Genomes data. The analytical results of RNA sequencing data were further validated by in vitro and in vivo experiments. Results: Withaferin A reduced the I/R injury-induced apoptotic death of HRMECs in vitro with a good drug-like property. RNA sequencing and experimental validation results indicated that withaferin A increased the production of the crucial antioxidant molecules heme oxygenase 1 (HO-1) and peroxiredoxin 1 (Prdx-1) during I/R. In addition, withaferin A activated the Akt signaling pathway and increased the expression of HO-1 and Prdx-1, thereby exerting an antioxidant effect, attenuated the retinal I/R injury, and decreased the apoptosis of HRMECs. The blockade of Akt completely abolished the effects of withaferin A. Conclusions: The study identified for the first time that withaferin A can protect against the I/R-induced apoptosis of human microvascular retinal endothelial cells via increasing the production of the antioxidants Prdx-1 and HO-1. Results suggest that withaferin A is a promising drug candidate for the treatment of retinal I/R injury. [ABSTRACT FROM AUTHOR]

Objective: NOV/CCN3 is an adipocytokine recently linked to obesity, insulin resistance, and cardiometabolic dysfunction. NOV is manufactured and secreted from adipose tissue, with blood levels highly correlated with BMI. NOV levels are increased in obesity and a myriad of inflammatory diseases. Elevated NOV levels cause oxidative stress by increasing free radicals, decreasing antioxidants, and decreasing heme oxygenase (HO-1) levels, resulting in decreased vascular function. Silencing NOV in NOV knockout mice improved insulin sensitivity. We wanted to study how suppressing NOV expression in an obese animal model affected pathways and processes related to obesity, inflammation, and cardiometabolic function. This is the first study to investigate the interaction of adipose tissue-specific NOV/CCN3 and cardiometabolic function. Methods: We constructed a lentivirus containing the adiponectin-promoter-driven shNOV to examine the effect of NOV inhibition (shNOV) in adipose tissue on the heart of mice fed a high-fat diet. Mice were randomly divided into three groups (five per group): (1) lean (normal diet), (2) high-fat diet (HFD)+ sham virus, and (3) HFD + shNOV lentivirus. Blood pressure, tissue inflammation, and oxygen consumption were measured. Metabolic and mitochondrial markers were studied in fat and heart tissues. Results: Mice fed an HFD developed adipocyte hypertrophy, fibrosis, inflammation, and decreased mitochondrial respiration. Inhibiting NOV expression in the adipose tissue of obese mice by shNOV increased mitochondrial markers for biogenesis (PGC-1α, the nuclear co-activator of HO-1) and functional integrity (FIS1) and insulin signaling (AKT). The upregulation of metabolic and mitochondrial markers was also evident in the hearts of the shNOV mice with the activation of mitophagy. Using RNA arrays, we identified a subgroup of genes that highly correlated with increased adipocyte mitochondrial autophagy in shNOV-treated mice. A heat map analysis in obese mice confirmed that the suppression of NOV overrides the genetic susceptibility of adiposity and the associated detrimental metabolic changes and correlates with the restoration of anti-inflammatory, thermogenic, and mitochondrial genes. Conclusion: Our novel findings demonstrate that inhibiting NOV expression improves adipose tissue function in a positive way in cardiometabolic function by inducing mitophagy and improving mitochondrial function by the upregulation of PGC-1α, the insulin sensitivity signaling protein. Inhibiting NOV expression increases PGC-1, a key component of cardiac bioenergetics, as well as key signaling components of metabolic change, resulting in improved glucose tolerance, improved mitochondrial function, and decreased inflammation. These metabolic changes resulted in increased oxygen consumption, decreased adipocyte size, and improved cardiac metabolism and vascular function at the structural level. The crosstalk of the adipose tissue-specific deletion of NOV/CCN3 improved cardiovascular function, representing a novel therapeutic strategy for obesity-related cardiometabolic dysfunction. [ABSTRACT FROM AUTHOR]

The activation of heme oxygenase 1 (HO-1)/carbon monoxide (CO) inhibits chronic inflammatory pain, but its role in the central nervous system (CNS) is not entirely known. We evaluated whether the treatment with an HO-1 inducer, cobalt protoporphyrin IX (CoPP), or a CO-releasing molecule, tricarbonyldichlororuthenium(II)dimer (CORM-2), modulates the nociceptive, apoptotic and/or oxidative responses provoked by persistent inflammatory pain in the CNS. In C57BL/6 male mice with peripheral inflammation caused by complete Freund's adjuvant (CFA), we assessed the effects of CORM-2 and CoPP on the expression of protein kinase B (Akt), the apoptotic protein BAX, and the antioxidant enzymes HO-1 and NADPH quinone oxidoreductase 1 (NQO1) in the periaqueductal gray matter (PAG), amygdala (AMG), ventral hippocampus (VHPC) and medial septal area (MSA). Our results showed that the increased expression of p-Akt caused by peripheral inflammation in the four analyzed brain areas was reversed by CORM-2 and CoPP therapies. Both treatments also normalized the upregulation of BAX induced by CFA on the VHPC and MSA. Oxidative stress, demonstrated with the decreased expression of HO-1 on the PAG and AMG, was normalized in CORM-2 and CoPP treated animals. CoPP also increased the expression of HO-1 on VHPC, and both treatments up-regulated the NQO1 levels on the PAG of CFA-injected animals. In conclusion, both CORM-2 and CoPP treatments inhibited the nociceptive and apoptotic responses generated by peripheral inflammation and/or potentiated the antioxidant responses in several brain areas revealing the new modulatory effects of these treatments in the CNS of animals with chronic inflammatory pain. • HO-1/CO activation inhibited chronic inflammatory pain and blocked Akt activation in the CNS. • CORM-2 and CoPP inhibited the apoptotic responses induced by peripheral inflammation in the VHPC and MSA. • CORM-2 and CoPP activated the antioxidant responses in the PAG and AMG of animals with persistent inflammatory pain. [ABSTRACT FROM AUTHOR]

Zingerone is a non‐volatile compound found mainly in dried ginger. Zingerone increases the expression of osteogenic markers and has antioxidant effects. A previous study showed that zingerone accelerated osteoblast differentiation by suppressing the expression of Smad7, a member of the inhibitory Smad (I‐Smad) family. However, it is not known if zingerone can induce osteoblast differentiation by regulating Smad1/5/9, a member of the receptor‐regulated Smad (R‐Smad) family. In addition, osteoblast differentiation induced by Smad1/5/9 mediated increases in the expression of heme oxygenase 1 (HO‐1) has not been reported. This study investigated the effects of zingerone on osteoblast differentiation and confirmed the relationship between Smad1/5/9 and HO‐1. Zingerone increased the expression of osteogenic genes including runt‐related transcription factor 2 (Runx2), distal‐less homeobox (Dlx5) and osteocalcin (OC) and also promoted Smad1/5/9 phosphorylation. Interestingly, HO‐1 expression was also elevated by zingerone, and an inhibitor of HO‐1 (Sn[IV] protoporphyrin IX dichloride [SnPP]) suppressed the zingerone‐induced increase in HO‐1 expression and expression of osteogenic marker genes such as Dlx5, Runx2 and OC. Protein phosphatase 2A Cα (PP2A Cα, an inhibitor of Smad1/5/9) suppressed the zingerone‐induced increase in HO‐1 expression and expression of osteogenic marker genes. The zingerone‐induced increase in HO‐1 luciferase activity was suppressed by PP2A Cα. Taken together; our data demonstrate that zingerone promotes osteoblast differentiation by increasing Smad1/5/9 mediated HO‐1 expression. [ABSTRACT FROM AUTHOR]

Background and Aim: Intestinal ischemia/reperfusion (II/R) can cause injury of remote organs, including acute renal injury. All of these, in turn, increase the rate of disability and mortality. Anwulignan (Anwu) is an active monomer from Schisandra sphenanthera, which has been used for thousands of years in China as a medical herb. In our previous study, we found that Anwu can improve the intestinal function after ischemia/reperfusion. Therefore, we were curious to know if Anwu can have a protective effect on remote organ injury after II/R. The purpose of the present study was to examine the effect of Anwu on the remote renal injury induced by II/R in rats and investigate its mechanism. Materials and Methods: Forty Sprague Dawley (SD) rats were divided into four groups, and they were sham operation (Sham), sham + Anwu, II/R, and II/R + Anwu groups. After reperfusion or sham operation, blood and kidneys were collected from the rats for the detection of relative biochemical parameters. Results: Renal indexes were not significantly different among all groups. In the II/R group the following were the findings: blood urea nitrogen and creatinine levels were increased, kidney injury score was increased, renal superoxide dismutase was reduced, the activities of reduced glutathione and catalase were decreased, the renal malondialdehyde content was increased, there was an improvement in the levels of renal proinflammatory cytokines, interleukin-6, tumor necrosis factor-α, and interleukin-1β, the expressions of renal oxidative stress-related p-Nrf2 and heme oxygenase (decycling) 1 (HO-1) were decreased, and the Kelch-like ECH-associated protein 1 (Keap1) expression was increased. The expression levels of the apoptotic protein, cleaved caspase-3, were raised, while the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated x protein (Bax) ratio was reduced. However, the administration of Anwu before the surgery significantly reversed the above changes. Conclusion: Anwu has a protective effect against the II/R-induced remote renal injury in rats, which may be related to its regulation of antioxidant, anti-inflammatory, and antiapoptotic pathways. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of erianin on the viability, migration, and invasion of KB cells and elucidate its underlying mechanisms. Methods: Cell Counting Kit-8, colony formation, wound healing, and Transwell assays were used to determine the proliferation, migration, and invasion of oral cancer KB cells. Furthermore, malondialdehyde (MDA) and glutathione (GSH) levels were determined. Fluorescent probes were used to detect changes in intracellular reactive oxygen species and iron ions. Additionally, the expressions of ferroptosis-related proteins, NF-E2-related factor 2 (Nrf2), ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and glutathione peroxidase 4 (GPX4) were analyzed by Western blotting assays. Results: Erianin induced ferroptosis and inhibited the proliferation, migration, and invasion of KB cells. Moreover, erianin decreased GSH level, increased MDA level, elevated intracellular ROS and Fe2+ contents, and downregulated the expression of the ferroptosisrelated proteins Nrf2, HO-1, GPX4, and FTH1 in KB cells. These effects of erianin were effectively reversed by a ferroptosis inhibitor, ferrostatin-1. Conclusions: Erianin inhibits the proliferation, migration, and invasion of oral cancer cells and induces ferroptosis via the Nrf2/ HO-1/GPX4 signaling pathway. Therefore, erianin may be a potential candidate for the treatment of oral cancer. [ABSTRACT FROM AUTHOR]

Particulate matter (PM) is one of the most dangerous pollutants in the air. Urban vegetation, especially trees and shrubs, accumulates PM and reduces its concentration in ambient air. The aim of this study was to examine 10 tree and shrub species common for the Indian city of Jodhpur (Rajasthan) located on the edge of the Thar Desert and determine (1) the accumulation of surface and in-wax PM (both in three different size fractions), (2) the amount of epicuticular waxes on foliage, (3) the concentrations of heavy metals (Cd and Cu) on/in the leaves of the examined species, and (4) the level of heme oxygenase enzyme in leaves that accumulate PM and heavy metals. Among the investigated species, Ficus religiosa L. and Cordia myxa L. accumulated the greatest amount of total PM. F. religiosa is a tall tree with a lush, large crown and leaves with wavy edge, convex veins, and long petioles, while C. myxa have hairy leaves with convex veins. The lowest PM accumulation was recorded for drought-resistant Salvadora persica L. and Azadirachta indica A. Juss., which is probably due to their adaptation to growing conditions. Heavy metals (Cu and Cd) were found in the leaves of almost every examined species. The accumulation of heavy metals (especially Cu) was positively correlated with the amount of PM deposited on the foliage. A new finding of this study indicated a potentially important role of HO in the plants' response to PM-induced stress. The correlation between HO and PM was stronger than that between HO and HMs. The results obtained in this study emphasise the role of plants in cleaning polluted air in conditions where there are very high concentrations of PM. [ABSTRACT FROM AUTHOR]

TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) orchestrate the cellular response to a variety of stressors, including nutrient deprivation, oxidative stress and pathogens. Here we describe a novel interaction of TFEB and TFE3 with the FAcilitates Chromatin Transcription (FACT) complex, a heterodimeric histone chaperone consisting of SSRP1 and SUPT16H that mediates nucleosome disassembly and assembly, thus facilitating transcription. Extracellular stimuli, such as nutrient deprivation or oxidative stress, induce nuclear translocation and activation of TFEB and TFE3, which then associate with the FACT complex to regulate stress-induced gene transcription. Depletion of FACT does not affect TFEB activation, stability, or binding to the promoter of target genes. In contrast, reduction of FACT levels by siRNA or treatment with the FACT inhibitor curaxin, severely impairs induction of numerous antioxidant and lysosomal genes, revealing a crucial role of FACT as a regulator of cellular homeostasis. Furthermore, upregulation of antioxidant genes induced by TFEB over-expression is significantly reduced by curaxin, consistent with a role of FACT as a TFEB transcriptional activator. Together, our data show that chromatin remodeling at the promoter of stress-responsive genes by FACT is important for efficient expression of TFEB and TFE3 targets, thus providing a link between environmental changes, chromatin modifications and transcriptional regulation. Abbreviations: ADNP2, ADNP homeobox 2; ATP6V0D1, ATPase H+ transporting V0 subunit d1; ATP6V1A, ATPase H+ transporting V1 subunit A; ATP6V1C1, ATPase H+ transporting V1 subunit C1; CSNK2/CK2, casein kinase 2; CLCN7, chloride voltage-gated channel 7; CTSD, cathepsin D; CTSZ, cathepsin Z; EBSS, earle's balanced salt solution; FACT complex, facilitates chromatin transcription complex; FOXO3, forkhead box O3; HEXA, hexosaminidase subunit alpha; HIF1A, hypoxia inducible factor 1 subunit alpha; HMOX1, heme oxygenase 1; LAMP1, lysosomal associated membrane protein 1; MAFF, MAF bZIP transcription factor F; MAFG, MAF bZIP transcription factor G; MCOLN1, mucolipin TRP cation channel 1; MTORC1, mechanistic target of rapamycin kinase complex 1; NaAsO2, sodium arsenite; POLR2, RNA polymerase II; PPARGC1A, PPARG coactivator 1 alpha; PYROXD1, pyridine nucleotide-disulfide oxidoreductase domain 1; RRAGC, Ras related GTP binding C; SEC13, SEC13 homolog, nuclear pore and COPII coat complex component; SLC38A9, solute carrier family 38 member 9; SSRP1, structure specific recognition protein 1; SUPT16H, SPT16 homolog, facilitates chromatin remodeling subunit; TFEB, transcription factor EB; TFE3, transcription factor binding to IGHM enhancer 3; TXNRD1, thioredoxin reductase 1; UVRAG, UV radiation resistance associated; WDR59, WD repeat domain 59. [ABSTRACT FROM AUTHOR]

1,3‐Dichloro‐2‐propanol (1,3‐DCP) is a representative chloropropane environmental contaminant with multiple toxicities. Ferroptosis is a novel iron‐dependent form of regulated cell death that is closely associated with the accumulation of lipid peroxides, Fe2+ and reactive oxygen species (ROS). In this study, we found that 1,3‐DCP could induce mouse liver injury via ferroptosis. Administrating of C57BL/6J mice with 12.5, 25, and 50 mg/kg 1,3‐DCP for 4 weeks via oral gavage, the data showed that 1,3‐DCP exposure led to the pathological changes in mouse livers, remarkably induced accumulation of malondialdehyde (MDA) and Iron, reduction of glutathione (GSH), and changed in the expression of ferroptosis marker proteins glutathione peroxidase 4 (GPX4) and acyl‐CoA synthetase‐4 (ACSL4). Then, we also proved the results with HepG2 cells in vitro. The data showed that treatment 1,3‐DCP significantly triggered the ferroptosis in vitro. Furthermore, we found that the ferroptosis‐related signal pathways were significantly activated in mice livers and HepG2 cells in response to 1,3‐DCP exposure. The data showed that 1,3‐DCP induced ferroptosis by inhibiting nuclear factor erythroid 2‐related factor 2 (Nrf2) translocation into nuclear and thereby suppressing the expression of its downstream target proteins including GPX4, ferritin heavy chain (FTH), ferroportin (FPN), cystine/glutamate transporter xCT (SLC7A11), and heme oxygenase 1 (HO‐1). Taken together, our findings confirmed that 1,3‐DCP induced ferroptosis via the Nrf2/ARE signaling pathway in hepatocytes. Our works provide new toxicity mechanisms of 1,3‐DCP with ferroptosis on hepatocytes injury. [ABSTRACT FROM AUTHOR]

The yellowing of green broccoli is a phenomenon that indicates a serious deterioration of freshness. The green broccoli has been more popular than the yellow one, with its higher nutritional value. Chitosan coating has been employed in vegetables for green-keeping, owing to its functions of regulating chlorophyll metabolism and antioxidant defense. Furthermore, selenium was commonly utilized in the pre-harvest of fruit and vegetables as an antioxidant and chlorophyll regulator. However, there have not yet been concerns about the effects of selenium-chitosan on vegetable yellowing. This study first investigated the impact of selenium-chitosan on the quality of fresh-cut broccoli yellowing during storage by analyzing the chromatic aberration and phytochromes. Additionally, then, the gene expression related to chlorophyll metabolism (POR, CAO, HO, CHLI, NYC1), carotenoid metabolism (VDE, CCS, LCYE, ZEP, HYD), and transcription factors (NAC92, ZIPPER, bHLH66, APL, PIF4) were analyzed using the RT-qPCR technique. Test results showed that treatment with selenium-chitosan can slow down the reduction in h° (Hue angle values) and reduce ethylene release rate and respiration intensity. Via the molecular approach, it was further identified that this treatment could inhibit chlorophyll degradation and carotenoid biosynthesis, accompanied by lower expression levels of heme oxygenase (HO), chlorophyllide A oxygenase (CAO), violaxanthin de-epoxidase (VDE), β-carotene 3-hydroxylase (HYD), NAC92, basic leucine zipper (ZIPPER), bHLH66, PIF4 and APL, and higher expression levels of magnesium chelatase subunit I (CHLI) and lycopene ε-cyclase (LCYE) genes. This work can be used to explore the molecular mechanism of selenium-chitosan in inhibiting the yellowing of fresh-cut broccoli. This study will be of great economic importance in marketing and export by increasing the shelf life of fruits and vegetables. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. To date, the main strategies to counteract its progression consist of focal radiation on the tumor site and ocular enucleation. Furthermore, many UM patients develop liver metastasis within 10 years following diagnosis, eventually resulting in a poorer prognosis for those patients. Dissecting the molecular mechanism involved in UM progression may lead to identify novel prognostic markers with significative clinical applications. The aim of the present study was to evaluate the role of Heme Oxygenase 1 (HO-1) in regulating UM progression. UM cell lines (92.1) were treated with Hemin (CONC e time), a strong inducer of HO-1, and VP13/47, a selective inhibitor of its enzymatic activity. Interestingly, our results showed an enhanced 92.1 cellular proliferation and wound healing ability following an HO-1 increase, overall unveiling the role played by this protein in tumor progression. Similar results were obtained following treatment with two different CO releasing molecules (CORM-3 and CORM-A1). These results were further confirmed in a clinical setting using our UM cohort. Our results demonstrated an increased median HO-1 expression in metastasizing UM when compared to nonmetastasizing patients. Overall, our results showed that HO-1 derived CO plays a major role in UM progression and HO-1 protein expression may serve as a potential prognostic and therapeutical factor in UM patients. [ABSTRACT FROM AUTHOR]

Gingival tissue experiences an environment of nutrient shortage, such as low glucose conditions, after periodontal surgery. Our previous studies found that this low glucose condition inhibits normal gingival cell functions. However, the mechanism by which this glucose-deficient environment causes cellular damage to human gingival fibroblasts (HGnFs) remains unclear. This study aimed to investigate the biological effects of ROS induction on HGnFs under low glucose conditions. ROS levels and cellular anti-ROS ability of HGnFs under different glucose concentrations were evaluated by measuring ROS formation and the expression of superoxide dismutase and heme oxygenase 1. Changes in cellular viability were investigated using 5-bromo-2′-deoxyuridine assay and cell survival detection, and the cellular damage was evaluated by the expression of inflammatory cytokines and changes in the expression of autophagy-related protein. ROS formation was then blocked using N-acetyl-L-cysteine (NAC), and the effects of ROS on HGnFs under low glucose conditions were investigated. Low glucose conditions induced ROS accumulation, reduced cellular activity, and induced inflammation and autophagy. After NAC application, the anti-ROS capacity increased, cellular activity improved, and inflammation and autophagy were controlled. This can be effectively controlled by the application of antioxidants such as NAC. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase ½ level. We identified small-molecule inducers of HO-1 that enable us to exploit the full therapeutic potential of HO-1, the combination of its products, and yet-undefined effects of the enzyme system. Through cell-based, high-throughput screens for induction of HO-1 driven by the human HO-1 promoter/enhancer, we identified two novel small molecules and broxaldine (an FDA-approved drug) for further consideration as candidate compounds exhibiting an Emax ≥70% of 5 µM hemin and EC50 <10 µM. RNA sequencing identified shared binding motifs to NRF2, a transcription factor known to regulate antioxidant genes, including HMOX1. In vitro, the cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of a candidate compound induced HO-1 expression in the kidneys of mice. This study serves as the basis for further development of small-molecule HO-1 inducers as preventative or therapeutic interventions for a variety of pathologies, including AKI. [ABSTRACT FROM AUTHOR]

Rhizoma Dioscoreae Bulbiferae (RDB) was effective on relieving cough and expectorant but accompanied by severe toxicity, especially in hepatotoxicity. A previous study found that processing with Angelicae Sinensis Radix (ASR) reduced RDB-induced hepatotoxicity. However, up to now, the optimized processing process of ASR-processed RDB has not been explored or optimized, and the detoxification mechanism is still unknown. This study evaluated the detoxification technology and possible mechanism of processing with ASR on RDB-induced hepatotoxicity. The optimized processing process of ASR-processed RDB was optimized by the content of diosbulbin B (DB), the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and histopathological analysis. The processing detoxification mechanism was evaluated by detecting the antioxidant levels of nuclear factor E2 related factor 2 (Nrf2) and its downstream heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO1), glutamylcysteine ligase catalytic subunit (GCLM), and the levels of downstream antioxidant factors of Nrf2. Besides, the antitussive and expectorant efficacy of RDB was also investigated. This work found that processing with ASR attenuated RDB-induced hepatotoxicity, which can be verified by reducing the levels of ALT, AST, and ALP, and reversing the pathological changes of liver histomorphology. And the optimized processing process of ASR-processed RDB is "processing at a mass ratio of 100:20 (RDB:ASR) and a temperature of 140°C for 10 min." Further results corroborated that the intervention of processed products of ASR-processed RDB remarkably upregulated the Nrf2/HO-1/NQO1/GCLM protein expression levels in liver, and conserved antitussive and expectorant efficacy of RDB. The above findings comprehensively indicated that the optimized processing process of ASR-processed RDB was "processing at a mass ratio of 100:20 (RDB:ASR) and a temperature of 140°C for 10 min," and the processing detoxification mechanism involved enhancing the level of Nrf2-mediated antioxidant defense in liver as a key target organ. [ABSTRACT FROM AUTHOR]

A new sesquiterpenoid (1) was obtained by hydrogenating Chlojaponilactone B. The structure of 1 was elucidated according to a combination of NMR, HRESIMS, and NOE diffraction data. The treatment of H2O2 in a PC12 cell model was used to evaluate the antioxidant activity of 1. An MMT assay showed that 1 had no cytotoxicity to the PC12 cell and rescued cell viability from the oxidative damage caused by H2O2. The treatment of 1 stabilized the mitochondria membrane potential (MMP), which decreased the intracellular ROS level and reduced cell apoptosis in the oxidative stress model. The activities of antioxidant enzyme superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the content of intracellular glutathione (GSH) were significantly enhanced after the treatment of 1. In addition, the results of qRT-PCR showed that 1 treatment minimized the cell injury by H2O2 via the up-regulation of the expression of nuclear factor erythroid 2 (Nrf2) and its downstream enzymes Heme oxygenase 1 (HO-1), glutamate cysteine ligase-modifier subunit (GCLm), and NAD(P)H quinone dehydrogenase 1 (Nqo1). Based on the antioxidant activity of 1, we speculated its potential as a therapeutic agent for some diseases induced by oxidative damage. [ABSTRACT FROM AUTHOR]

Sparstolonin B (SsnB), which is found in Sparganium stoloniferum, prevents the synthesis of inflammatory mediators and is related to functional pathways of survival. In this study, we assessed the possible protective functions of SsnB on lipopolysaccharide (LPS)-induced inflammatory responses. We determined the functions of SsnB on controlling heme oxygenase (HO)-1, cyclooxygenase (COX-)2, and inducible nitric oxide synthase (iNOS) in LPS-activated human umbilical vein endothelial cells (HUVECs). Furthermore, the distinct function of SsnB on the expression of iNOS and well-known pro-inflammatory mediators, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, were assessed in the pulmonary histological status of LPS-injected mice. SsnB upregulated the HO-1 production, inhibited luciferase-NF-κB interaction, and lowered COX-2/PGE2 and iNOS/NO, which lead to the reduction of STAT-1 phosphorylation. Moreover, SsnB enhanced the nuclear translocation of Nrf2, elevated the binding activity between Nrf2 and antioxidant response elements (AREs), and weakened IL-1β expression on LPS-treated HUVECs. SsnB-suppressed iNOS/NO synthesis was restored by the process of the RNAi inhibition of HO-1. In experiment with an LPS-injected animal model, SsnB remarkably decreased the iNOS expression in the pulmonary biostructure and TNF-α level in the bronchoalveolar lavage fluid (BALF). Therefore, these results demonstrate that SsnB is responsible for inflammation ameliorative activity by controlling iNOS through inhibition of both NF-κB expression and p-STAT-1. Therefore, SsnB could be a candidate for promoting novel clinical substances to remedy pathologic inflammation. [ABSTRACT FROM AUTHOR]

Heme (iron-protoporphyrin IX) is an essential but potentially toxic cellular cofactor. While most organisms are heme prototrophs, many microorganisms can utilize environmental heme as iron source. The pathogenic yeast Candida albicans can utilize host heme in the iron-poor host environment, using an extracellular cascade of soluble and anchored hemophores, and plasma membrane ferric reductase-like proteins. To gain additional insight into the C. albicans heme uptake pathway, we performed an unbiased genetic selection for mutants resistant to the toxic heme analog Ga3+-protoporphyrin IX at neutral pH, and a secondary screen for inability to utilize heme as iron source. Among the mutants isolated were the genes of the pH-responsive RIM pathway, and a zinc finger transcription factor related to S. cerevisiae HAP1. In the presence of hemin in the medium, C. albicans HAP1 is induced, the Hap1 protein is stabilized and Hap1-GFP localizes to the nucleus. In the hap1 mutant, cytoplasmic heme levels are elevated, while influx of extracellular heme is lower. Gene expression analysis indicated that in the presence of extracellular hemin, Hap1 activates the heme oxygenase HMX1, which breaks down excess cytoplasmic heme, while at the same time it also activates all the known heme uptake genes. These results indicate that Hap1 is a heme-responsive transcription factor that plays a role both in cytoplasmic heme homeostasis and in utilization of extracellular heme. The induction of heme uptake genes by C. albicans Hap1 under iron satiety indicates that preferential utilization of host heme can be a dietary strategy in a heme prototroph. Author summary: The yeast Candida albicans is a human commensal organism, as well as an important opportunistic systemic pathogen. During tissue invasion, systemic pathogens are confronted with iron scarcity, which they can overcome by scavenging host heme as iron source. It was however not known whether C. albicans can sense the presence of host heme independently of iron sensing. Using a forward genetics approach, we identified a transcription factor that regulates both homeostasis of internal heme and uptake of external heme. This transcription factor allows activation of the heme uptake pathway even in iron-rich medium, suggesting that heme can be a preferred iron source over elemental iron, and that heme prototrophs can scavenge host heme as a source for cellular heme. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Given the high relapse rate, more effective treatments are needed to improve clinical outcomes. We previously demonstrated that heme oxygenase 1 (HO1) is overexpressed in AML, while the functional roles of HO1 remain unclear.Methods: Bioinformatics analysis and flow cytometry were conducted to assess the association between HO1 levels and immune cells or immune checkpoint/ligand molecules in AML patients. Primary natural killer (NK) cells were purified and subsequently co-cultured in vitro with transduced AML cells to determine the effects of HO1 expression on NK cell functions. AML mice models were established to investigate the effects of HO1 expression on cytotoxic effects of NK cells in vivo. The molecular mechanism was studied by flow cytometry, quantitative real-time PCR (qRT-PCR), western blotting, and immunoprecipitation.Results: Bioinformatics analysis indicated a correlation between HO1 expression and the AML immune microenvironment. The present study findings indicated that HO1 specifically downregulates the expression of CD48, a ligand of the NK cell-activating receptor 2B4, thus decreasing the cytotoxic effect of NK cells. HO1 overexpression promoted tumor growth and inhibited the cytotoxic effect of NK cells in the AML mice model. Mechanistic investigations found that HO1 directly interacted with Sirt1 and increased its expression and deacetylase activity. With the overexpression of HO1, increased Sirt1 in AML cells enabled histone H3K27 deacetylation to suppress CD48 transcription and expression. Administration of Sirt1 inhibitor restored the expression of CD48.Conclusions: Collectively, HO1 promotes NK cell dysfunction in AML. Therefore, restoring NK cell function by inhibiting HO1 activity is a potential immunotherapeutic approach against AML. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD) are chronic, recurring gastrointestinal diseases that severely impair health and quality of life. Although therapeutic options have significantly expanded in recent years, there is no effective therapy for a complete and permanent cure for IBD. Well tolerated dietary interventions to improve gastrointestinal health in IBD would be a welcome advance especially with anticipated favorable tolerability and affordability. Soluble protein hydrolysate (SPH) is produced by the enzymatic hydrolysis of commercial food industry salmon offcuts (consisting of the head, backbone and skin) and contains a multitude of bioactive peptides including those with anti-oxidant properties. This study aimed to investigate whether SPH ameliorates gastrointestinal injury in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model. Mice were randomly assigned to four groups: Control (no colitis), Colitis, Colitis/CP (with control peptide treatment), and Colitis/SPH (with SPH treatment). Colitis was induced by cutaneous sensitization with 1% TNBS on day −8 followed by 2.5% TNBS enema challenge on day 0. Control peptides and SPH were provided to the mice in the Colitis/CP or Colitis/SPH group respectively by drinking water at the final concentration of 2% w/v daily from day −10 to day 4. Then, the colon was harvested on day 4 and examined macro- and microscopically. Relevant measures included disease activity index (DAI), colon histology injury, immune cells infiltration, pro- and anti-inflammatory cytokines and anti-oxidative gene expression. It was found that SPH treatment decreased the DAI score and colon tissue injury when compared to the colitis-only and CP groups. The protective mechanisms of SPH were associated with reduced infiltration of CD4+ T, CD8+ T and B220+ B lymphocytes but not macrophages, downregulated pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6), and upregulated anti-inflammatory cytokines (transforming growth factor-β1 and interleukin-10) in the colon tissue. Moreover, the upregulation of anti-oxidative genes, including ferritin heavy chain 1, heme oxygenase 1, NAD(P)H quinone oxidoreductase 1, and superoxide dismutase 1, in the colons of colitis/SPH group was observed compared with the control peptide treatment group. In conclusion, the protective mechanism of SPH is associated with anti-inflammatory and anti-oxidative effects as demonstrated herein in an established mice model of colitis. Clinical studies with SPH as a potential functional food for the prevention or as an adjuvant therapy in IBD may add an effective and targeted diet-based approach to IBD management in the future. [ABSTRACT FROM AUTHOR]

Background: We recently demonstrated that oxygen-glucose deprivation (OGD) and unconjugated bilirubin (UCB) can damage mature and immature organotypic hippocampal slices and induce an oxidative stress similar to what occurs in jaundiced term and preterm infants with hypoxic-ischemic encephalopathy (HIE). Objectives: To assess the effects of OGD and UCB on the expression of heme-oxygenase 1 (HO-1) and oxidative stress-related enzymes in an in vitro model of HIE. Methods: Mature and immature organotypic hippocampal slices were exposed to 30-min OGD and to 24 h UCB or UCB plus human serum albumin (HSA). The expression of HO-1, superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase (GPX), and nuclear factor erythroid-related factor 2 were analyzed by real-time PCR. Results: In mature slices, OGD did not affect the expression of HO-1 and oxidative stress-induced enzymes. The addition of UCB was associated with the upregulation of HO-1 and Nrf2 that is abolished by the presence of equimolar amount of HSA. In immature slices, OGD induced the downregulation of CAT, GPX, and Nrf2 expression and the addition of UCB further decreased GPX. The addition of UCB and HSA reverted the effects of OGD and UCB on gene expression. Conclusions: In an in vitro model of HIE in term infants, we did not observe neuroprotective changes of the expression of HO-1 and genes involved in antioxidant defenses. Conversely, in an in vitro model of HIE in preterm infants, we observed a harmful decrease of the expression of genes encoding for antioxidant enzymes. [ABSTRACT FROM AUTHOR]

To distinguish the influences of fuel type and truck speed on chemical composition and sub-toxic effects of particulates (PM2.5) from engine emissions, biomarkers—interleukin-6 (IL-6), cytochrome P450 (CYP) 1A1, heme oxygenase (HO)-1, and NADPH-quinone oxidoreductase (NQO)-1—were studied in A549 human lung cells. Fuel type and truck speed preferentially affected the quantity and ion/polycyclic aromatic hydrocarbon (PAH) composition of PM2.5, respectively. Under idling operation, phenanthrene was the most abundant PAH. At high speed, more than 50% of the PAHs had high molecular weight (HMW), of which benzo[a]pyrene (B[a]P), benzo[ghi]perylene (B[ghi]P), and indeno[1,2,3-cd]pyrene (I[cd]P) were the main PAHs. B[a]P, B[ghi]P, and I[cd]P caused potent induction of IL-6, CYP1A1, and NQO-1, whereas phenanthrene mildly induced CYP1A1. Based on the PAH-mediated induction, the predicted increases in biomarkers were positively correlated with the measured increases. HMW-PAHs contribute to the biomarker induction by PM2.5, at high speed, which was reduced by co-exposure to epigallocatechin-3-gallate. [ABSTRACT FROM AUTHOR]

Patients with obstructive sleep apnea (OSA) have an increased risk of cardiovascular disease (CVD). Nitric oxide (NO) and heme oxygenase-1 (HO-1) affect vascular tone and are vasoprotective. Furthermore, hydrogen sulfide (H2S), an HO-1 inducer, is known to be a major effector molecule driving apneas. This study was conducted to examine the molecular relationships between these gasotransmitters and HO-1 in patients with OSA. Individuals who presented for evaluation for possible OSA were recruited and underwent overnight polysomnography. Individuals with an apnea-hypopnea index (AHI) of >5 per hour (OSA diagnosis) were considered cases (n = 19), while those with an AHI of <5 per hour (n = 6) were the controls. Blood samples were obtained before sleep and again from OSA cases prior to initiating treatment. H2S, NO, and HO-1 levels were assayed. Patients with OSA showed lower NO and H2S levels at baseline compared to controls. NO levels further decreased significantly from baseline in patients at the time of OSA diagnosis, while H2S levels largely showed an increasing trend, which was observed only when the subjects showing a baseline H2S level of >0.5 μM were excluded. Interestingly, analysis of HO-1 did not show a significant change from baseline, confirming the inverse relationship between the two gasotransmitters. The alterations in the bioavailability of endogenous H2S and its molecular interactions with NO and HO-1 regulating vascular tone may play a role in the pathogenesis of CVD in OSA patients. [ABSTRACT FROM AUTHOR]

Objective：To investigate the improvement effect of Phellinus igniarius acidic polysaccharide （PIP） on liver fibrosis in the mice induced by bile duct ligation （BDL），and to clarify its possible mechanism. Methods：A total of sixty 4-week-old male C57/BL6 mice were randomly divided into control group，model group，positive drug group，and PIP group，with 15 mice in each group. The mice in control group only received the passed surgical line without ligation around the common bile duct，and the bile duct of mice in model group，postive drug group and PIP group were ligated. After administration for 3 weeks， the blood was taken from eyeball 12 h after the last administration，and the mice were sacrificed. The body weights and liver weights of mice were weighed，and the liver index was calculated. Microplate method was used to determine the levels of alanine aminotransferase（ALT）and aspartate aminotransferase（AST）in serum of the mice in various goups；the levels of type Ⅲ procollagen（PC Ⅲ）and cellagen type Ⅳ（Col Ⅳ） in serum were determined by double antibody sandwich method. HE staining and Sirius red staining were used to observe the pathomorphology and fibrosis degrees of liver tissue of the mice in various groups；the activities of superoxide dismutase （SOD） and glutathione peroxidase （GSH-Px） and the levels of malondialdehyde （MDA）and glutathione （GSH） in liver tissue of the mice in various groups were determined. The expression levels of nuclear factor-E2 related factor（Nrf2），heme oxygenase-1（HO-1） and quinone oxidoreductase 1（NQO1）proteins in liver tissue of the mice in various groups were detected by Western blotting method. Results：Compared with control group，the body weight of the mice in model group had no significant difference（P>0. 05），and the liver weight and liver index were increased（P< 0. 05）；compared with model group，the body weight of the mice in PIP group had no significant change （P>0. 05），and the liver weight and liver index were decreased（P<0. 05）. The HE staining results showed no abnormalities in liver tissue of the mice in control group；the liver lobular structure was destroyed and focal liquefied hepatic necrosis and more inflammatory cell infiltration were seen in liver tissue of the mice in model group；compared with model group，the necrosis degrees of liver tissue of the mice in positive drug group and PIP group were significantly reduced， and the infiltration of inflammatory cells was reduced. The Sirius red staining results showed that compared with control group，the content of collagen fibers in liver tissue of the mice in model group was significantly increased；compared with model group，the content of collagen fibers in liver tissue of the mice in PIP group was significantly decreased. Compared with control group ，the ALT and AST levels in serum of the mice in model group were increased（P<0. 01）， PC Ⅲ and Col Ⅳ levels were increased（P<0. 05），the activities of SOD and GSH-Px were significantly decreased（P<0. 01），and the levels of MDA and GSH were significantly increased（P<0. 05 or P<0. 01）； compared with model group，the levels of ALT and AST in serum of the mice in positive drug group and PIP group were significantly decreased （P<0. 01），the levels of PC Ⅲ and Col Ⅳ were significantly decreased（P<0. 05 or P<0. 01），the activities of SOD and GSH-Px in liver tissue of the mice were increased（P<0. 05），and the levels of GSH and MDA were decreased（P<0. 05）. The Western blotting results showed that compared with control group，the expression levels of Nrf2，HO-1，and NQO1 proteins in liver tissue of the mice in model group were decreased（P<0. 05）；compared with model group，the expression levels of Nrf2，HO-1，and NQO1 proteins in liver tissue of the mice in PIP group were significantly increased（P<0. 05 or P<0. 01）. Conclusion：PIP can improve the liver fibrosis in the mice caused by BDL，and its mechanism may be related to reducing the level of liver oxidative stress and regulating the expression levels of Nrf2，HO-1 and NQO1 proteins in Nrf2 / HO-1 signaling pathway. [ABSTRACT FROM AUTHOR]

Arabidopsis thaliana heme oxygenase‐1 (AtHO‐1), a metabolic enzyme in the heme degradation pathway, serves as a prototype for study of the bilin‐related functions in plants. Past biological analyses revealed that AtHO‐1 requires ferredoxin‐NADP+ reductase (FNR) and ferredoxin for its enzymatic activity. Here, we characterized the binding and degradation of heme by AtHO‐1, and found that ferredoxin is a dispensable component of the reducing system that provides electrons for heme oxidation. Furthermore, we reported the crystal structure of heme‐bound AtHO‐1, which demonstrates both conserved and previously undescribed features of plant heme oxygenases. Finally, the electron transfer pathway from FNR to AtHO‐1 is suggested based on the known structural information. [ABSTRACT FROM AUTHOR]

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(1) Background: Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant, and it is receiving increasing attention regarding its human health risks due to its extensive use. Endothelial dysfunction is a mark of cardiovascular disease, but the basic mechanism of PFOS-induced endothelial dysfunction is still not fully understood. Ferroptosis is a newly defined regulatory cell death driven by cellular metabolism and iron-dependent lipid peroxidation. Although ferroptosis has been shown to be involved in the pathogenesis of cardiovascular diseases, the involvement of ferroptosis in the pathogenesis of endothelial dysfunction caused by PFOS remains unclear. (2) Purpose: To explore the role of ferroptosis in the dysfunction of endothelial cells and underlying mechanisms. (3) Methods: Human umbilical vein endothelial cells (HUVECs) were exposed to PFOS or PFOS and Fer-1. The viability, morphology change under electronic microscope, lipid-reactive oxygen species (lipid-ROS), and production of nitric oxide (NO) were determined. The expression of glutathione peroxidase 4(GPX4), ferritin heavy chain protein 1 (FTH1), heme oxygenase 1 (HO-1) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) were analyzed via Western blot analysis. (4) Results: PFOS was shown to cause a decrease in viability and morphological changes of mitochondria, and well as an increase in lipid droplets. The expression of GPX4, FTH1 and HO-1 was decreased, and that of ACSL4 was increased after exposure to PFOS. In addition to the above-mentioned ferroptosis-related manifestations, there was also a reduction in NO content. (5) Conclusions: PFOS induces ferroptosis by regulating the GPX4 and ACSL4 pathways, which leads to HUVEC dysfunction. [ABSTRACT FROM AUTHOR]

Arsenic exposure has been associated with the risks of various diseases, including cancers and metabolic diseases. The aim of this study was to examine the effects of arsenic exposure via drinking water on the expression of heme oxygenase-1 (HO-1), a major responsive gene to arsenic-induced oxidative stress, in mouse intestinal epithelial cells which is the first site of exposure for ingested arsenic, and the liver, a known target of arsenic toxicity. The expression of HO-1 was determined at mRNA, protein, or enzymic activity levels in mice exposed to sodium arsenite through drinking water, at various doses (0, 2.5, 10, 25, 100 ppm), and for various time periods (1, 3, 7, or 28 days). HO-1 was significantly induced in the intestine, but not liver, at arsenic doses of 25 ppm or lower. The intestinal HO-1 induction was seen in both males and females, plateaued within 1–3 days of exposure, and was accompanied by increases in microsomal HO activity. In mice exposed to 25-ppm of arsenite for 7 days, total arsenic and As(III) levels in intestinal epithelial cells were significantly higher than in the liver. These findings identify intestinal epithelial cells as likely preferential targets for arsenic toxicity and support further studies on the functional consequences of intestinal HO-1 induction. [ABSTRACT FROM AUTHOR]

The beneficial effects of Korean red ginseng extract (KRGE) on the central nervous system (CNS) have been reported. Among the CNS cells, astrocytes possess robust antioxidative properties and regenerative potential. Under physiological conditions, biliverdin reductase A (BVR-A) converts biliverdin (a heme oxygenase metabolite) into bilirubin, a major natural and potent antioxidant. We found that KRGE enhanced BVR-A in astrocytes in the fimbria region of the adult mouse hippocampus under physiological conditions. KRGE-induced BVR-A expression and subsequent bilirubin production were required for changes in mitochondrial membrane potential, mitochondrial mass, and oxidative phosphorylation through liver kinase B1 (LKB1), estrogen-related receptor α (ERRα), and sirtuin (SIRT1 and SIRT5) in astrocytes. However, BVR-A did not affect the KRGE-induced expression of AMP-activated protein kinase α (AMPKα). The KRGE-stimulated BVR-A–LKB1–SIRT1–ERRα pathway regulates the levels of mitochondria-localized proteins such as SIRT5, translocase of the outer mitochondrial membrane 20 (Tom20), Tom22, cytochrome c (Cyt c), and superoxide dismutase 2 (SOD2). Increased Tom20 expression in astrocytes of the hippocampal fimbria region was observed in KRGE-treated mice. KRGE-induced expression of Cyt c and SOD2 was associated with the Tom20/Tom22 complex. Taken together, KRGE-induced bilirubin production is required for enhanced astrocytic mitochondrial function in an LKB1-dependent and AMPKα-independent manner under physiological conditions. [ABSTRACT FROM AUTHOR]

Oligodendrocytes (OLs) of the central nervous system require iron for proteolipid biosynthesis during the myelination process. Although most heme is found complexed to hemoglobin in red blood cells, surprisingly, we found that Slc48a1, encoding the heme transporter Hrg1, is expressed at higher levels in OLs than any other cell type in rodent and humans. We confirmed in situ that Hrg1 is expressed in OLs but not their precursors (OPCs) and found that Hrg1 proteins in CNS white matter co-localized within myelin sheaths. In older Hrg1 null mutant mice we observed reduced expression of myelin associated glycoprotein (Mag) and ultrastructural myelin defects reminiscent of Mag-null animals, suggesting myelin adhesion deficiency. Further, we confirmed reduced myelin iron levels in Hrg1 null animals in vivo, and show that OLs in vitro can directly import both the fluorescent heme analogue ZnMP and heme itself, which rescued iron deficiency induced inhibition of OL differentiation in a heme-oxidase-dependent manner. Together these findings indicate OL Hrg1 encodes a functional heme transporter required for myelin integrity., (© 2024 The Author(s). GLIA published by Wiley Periodicals LLC.)

Background: Patients with sickle cell disease (SCD) experience intravascular hemolysis, leading to elevated plasma heme levels. This phenomenon has been associated with increased priapism in men with SCD. The heme group can be metabolized by heme oxygenase (HO), generating carbon monoxide (CO), which is known to promote smooth muscle relaxation via soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP). However, the effects of heme on the relaxation responses of corpus cavernosum (CC) have not been investigated., Objectives: To evaluate the functional and biochemical effects of the heme group on mouse CC smooth muscle in vitro., Materials and Methods: Male C57BL/6 mice were used. CC tissues were mounted in organ baths. Measurement of cGMP in mice CC was evaluated., Results: The cumulative addition of heme concentrations promoted the relaxation of CC. HO inhibitor (1J, 100 μM) or sGC inhibitor (ODQ, 10 μM) blocked the relaxing effect of the heme group. Pre-incubation of CC with heme (100 μM) enhanced relaxation induced by acetylcholine, sodium nitroprusside, and nitrergic relaxation (electrical field stimulation), which was abolished by 1J or ODQ. The heme group increased the cGMP production in CC, which was abolished by 1J or ODQ. cGMP levels were significantly higher in CC treated with heme, and pre-incubation with compound 1J or ODQ abolished the effect of heme in raising cGMP levels., Discussion and Conclusion: The HO-CO-sGC-cGMP pathway appears to play a crucial role in promoting CC relaxation. Our study provides novel insight into the role of group heme in CC relaxation and its potential contribution to priapism in SCD. Heme may serve as a pharmacological target for new therapies to prevent priapism., (© 2024 American Society of Andrology and European Academy of Andrology.)

Heme oxygenase (HO) is an enzyme that catalyzes heme degradation. HO dysfunction is linked to various pathological conditions, including diabetes. Results of animal studies indicate that HO expression and activity are downregulated in experimentally induced diabetes. This is associated with severe hormonal and metabolic disturbances. However, these pathological changes have been shown to be reversed by therapy with HO activators. In animals with experimentally induced diabetes, HO was upregulated by genetic manipulation or by pharmacological activators such as hemin and cobalt protoporphyrin. Induction of HO alleviated elevated blood glucose levels and improved insulin action, among other effects. This effect resulted from beneficial changes in the main insulin-sensitive tissues, i.e., the skeletal muscle, the liver, and the adipose tissue. The action of HO activators was due to positive alterations in pivotal signaling molecules and regulatory enzymes. Furthermore, diabetes-related oxidative and inflammatory stress was reduced due to HO induction. HO upregulation was effective in various animal models of type 1 and type 2 diabetes. These data suggest the possibility of testing HO activators as a potential tool for alleviating hormonal and metabolic disorders in people with diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background: Carbon monoxide (CO), influences ovarian function, pregnancy, and placental health. Heme oxygenase (HO)-1 and its products, including CO, exhibit protective and anti-inflammatory properties., Objective: This study investigates the protective effects of CO released by the carbon dioxide-releasing molecule (CORM)-2 against oxidative stress, functional and structural changes of the ovaries, and HO-1 expressions in female rats suffering from polycystic ovary syndrome (PCOS)., Materials and Methods: In this experimental study, 24 Rattus norvegicus var. Albinus female rats (180-200 gr, 8 wk) were randomly divided into 4 groups (n = 6/each): control, CORM-2 (10 mg/kg), PCOS (induced by 4 mg/kg, intramuscular injection and a single dose of estradiol valerate), PCOS + CORM-2. Ovary histological changes were evaluated by crystal violet staining. Malondialdehyde (MDA) level and superoxide dismutase (SOD) activity of ovarian tissue were assessed using enzyme-linked immunosorbent assay. HO-1 expression was evaluated using Western blot., Results: Corpus luteal formation significantly decreased in the PCOS group and was significantly restored with CORM-2 administration compared to the control group (p < 0.05). The expression of ovarian HO-1 protein was reduced in the PCOS group compared to controls (p < 0.01), and administration of CORM in PCOS rats significantly increased its expression (p < 0.0001). In addition, CORM administration markedly reduced ovarian MDA levels and restored SOD activity (p < 0.0001)., Conclusion: CORM-2 administration to PCOS rats created protective effects by reducing oxidative stress (reducing MDA level and restoring SOD activity) and increasing ovarian HO-1 protein., Competing Interests: All of the authors declare no conflict of interest., (Copyright © 2024 Asadi et al.)