• Autophagy
• Heme
• Interleukin 33
• Progesterone receptor
• Uterine endometrial cancer

• Female
• Humans
• Macrophages/metabolism
• Macrophages/drug effects
• Heme/metabolism
• Interleukin-33/metabolism
• Interleukin-33/genetics
• Progesterone/pharmacology
• Endometrial Neoplasms/metabolism
• Endometrial Neoplasms/drug therapy
• Endometrial Neoplasms/pathology
• Endometrial Neoplasms/genetics
• Receptors, Progesterone/metabolism
• Receptors, Progesterone/genetics
• Drug Resistance, Neoplasm
• Cell Line, Tumor
• Signal Transduction
• Gene Expression Regulation, Neoplastic
• Autophagy

• HO-1
• hypoxia
• immunomodulation
• metastasis
• oxidative stress
• prostate cancer (PC)
• therapeutic strategy
• therapy resistance

• Humans
• Heme Oxygenase-1/metabolism
• Heme Oxygenase-1/genetics
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/therapy
• Prostatic Neoplasms/genetics
• Male
• Tumor Microenvironment
• Gene Expression Regulation, Neoplastic
• Animals
• Cell Proliferation

• Haem oxygenase-1
• MFE
• Translation efficiency
• codon deoptimization
• codon optimization
• codon pair deoptimization
• codon pair optimization
• tAI

• antioxidant
• apoptosis
• autophagy
• cancer
• chemoresistance
• cytoprotective effect
• heme oxygenase-1 (HO-1)
• reactive oxygen species

• 81872432 National Natural Science Foundation of China

• acute myeloid leukemia
• heme oxygenase-1
• human leukocyte antigen-C
• natural killer cells

• SU-DHL-2 cell line
• diffuse large B-cell lymphoma
• ferroptosis
• propolis
• proteomics

• Metabolomics
• Osteosarcoma
• Transcriptomics
• Tumor microenvironment

• Acute myeloid leukemia (AML)
• Brahma related gene 1 (BRG1)
• Cytarabine (Ara-C)
• Drug resistance
• Heme oxygenase-1 (HO-1)
• Mitogen- and stress-activated protein kinase 1 (MSK1)

• Humans
• Leukemia, Myeloid, Acute/genetics
• Leukemia, Myeloid, Acute/drug therapy
• Leukemia, Myeloid, Acute/pathology
• Cytarabine/pharmacology
• Drug Resistance, Neoplasm/genetics
• Drug Resistance, Neoplasm/drug effects
• Heme Oxygenase-1/genetics
• Heme Oxygenase-1/metabolism
• Up-Regulation/drug effects
• Ribosomal Protein S6 Kinases, 90-kDa/metabolism
• Ribosomal Protein S6 Kinases, 90-kDa/genetics
• Apoptosis/drug effects
• Apoptosis/genetics
• Male
• Cell Line, Tumor
• Female
• U937 Cells
• Middle Aged
• THP-1 Cells
• Gene Expression Regulation, Leukemic/drug effects
• Adult

Background: Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation.

Methods: Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset (n = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and “stepAIC” algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset (n = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the “pRRophetic” and “TIDE” algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI.

Results: The FRGPI was established based on the HMOX1, TFRC, JUN, and SOCS1 genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high PD-L1 expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4⁺ T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4⁺ T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified.

Conclusion: FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.

Heme oxygenase 1 (HO-1) plays a key role in cell adaptation to stressors through the antioxidant, antiapoptotic, and anti-inflammatory properties of its metabolic products. For these reasons, in cancer cells, HO-1 can favor aggressiveness and resistance to therapies, leading to poor prognosis/outcome. Genetic polymorphisms of HO-1 promoter have been associated with an increased risk of cancer progression and a high degree of therapy failure. Moreover, evidence from cancer biopsies highlights the possible correlation between HO-1 expression, pathological features, and clinical outcome. Indeed, high levels of HO-1 in tumor specimens often correlate with reduced survival rates. Furthermore, HO-1 modulation has been proposed in order to improve the efficacy of antitumor therapies. However, contrasting evidence on the role of HO-1 in tumor biology has been reported. This review focuses on the role of HO-1 as a promising biomarker of cancer progression; understanding the correlation between HO-1 and clinical data might guide the therapeutic choice and improve the outcome of patients in terms of prognosis and life quality.

• HO-1
• Nrf2
• biomarker
• cancer progression
• patients
• prognosis
• therapy

• angiogenesis
• cancer
• cytoprotection
• heme oxygenase-1 (HO-1)
• metastasis
• tumor associated macrophages (TAMs)
• tumor immunology

• obesity
• t cells
• immunotherapy
• fructose
• ho-1

• Animals
• Antineoplastic Agents, Immunological/therapeutic use
• Carcinoma
• Cell Line, Tumor
• Cytoprotection
• Drug Resistance, Neoplasm
• Female
• Fructose/metabolism
• Heme Oxygenase-1/metabolism
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Tumor Escape

• F30 DK118873 NIDDK NIH HHS
• P30 CA091842 NCI NIH HHS
• R01 CA238705 NCI NIH HHS

The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely studied in proinflammatory diseases because treatments that overexpress this enzyme promote the generation of anti-inflammatory products. However, neonatal jaundice (hyperbilirubinemia) derived from HO overexpression led to the development of inhibitors, such as those based on metaloproto- and meso-porphyrins inhibitors with competitive activity. Further, non-competitive inhibitors have also been identified, such as synthetic and natural imidazole-dioxolane-based, small synthetic molecules, inhibitors of the enzyme regulation pathway, and genetic engineering using iRNA or CRISPR cas9. Despite most of the applications of the HO inhibitors being related to metabolic diseases, the beneficial effects of these molecules in immune-mediated diseases have also emerged. Different medical implications, including cancer, Alzheimer´s disease, and infections, are discussed in this article and as to how the selective inhibition of HO isoforms may contribute to the treatment of these ailments.

• cancer
• heme oxygenase-1
• heme oxygenase-2
• immunomodulation
• infections
• inhibitors

• Alzheimer Disease/metabolism
• Alzheimer Disease/prevention & control
• Animals
• Dioxolanes/metabolism
• Dioxolanes/pharmacology
• Enzyme Inhibitors/metabolism
• Enzyme Inhibitors/pharmacology
• Heme Oxygenase (Decyclizing)/antagonists & inhibitors
• Heme Oxygenase (Decyclizing)/metabolism
• Heme Oxygenase-1/antagonists & inhibitors
• Heme Oxygenase-1/metabolism
• Humans
• Imidazoles/metabolism
• Imidazoles/pharmacology
• Neoplasms/metabolism
• Neoplasms/prevention & control

• bilirubin
• marker
• prognosis
• traumatic brain injury

• Adult
• Bilirubin/blood
• Brain Injuries, Traumatic/blood
• Brain Injuries, Traumatic/diagnostic imaging
• Brain Injuries, Traumatic/mortality
• Case-Control Studies
• Central Nervous System Diseases/metabolism
• China/epidemiology
• Female
• Glasgow Coma Scale/trends
• Humans
• L-Lactate Dehydrogenase/metabolism
• Male
• Middle Aged
• Prognosis
• Retrospective Studies
• Risk Factors
• Severity of Illness Index

Central nervous system tumors are the most common pediatric solid tumors and account for 20–25% of all childhood malignancies. Several lines of evidence suggest that brain tumors show altered redox homeostasis that triggers the activation of various survival pathways, leading to disease progression and chemoresistance. Among these pathways, heme oxygenase-1 (HO-1) plays an important role. HO-1 catalyzes the enzymatic degradation of heme with the simultaneous release of carbon monoxide (CO), ferrous iron (Fe²⁺), and biliverdin. The biological effects of HO-1 in tumor cells have been shown to be cell-specific since, in some tumors, its upregulation promotes cell cycle arrest and cellular death, whereas, in other neoplasms, it is associated with tumor survival and progression. This review focuses on the role of HO-1 in central nervous system malignancies and the possibility of exploiting such a target to improve the outcome of well-established therapeutic regimens. Finally, several studies show that HO-1 overexpression is involved in the development and resistance of brain tumors to chemotherapy and radiotherapy, suggesting the use of HO-1 as an innovative therapeutic target to overcome drug resistance. The following keywords were used to search the literature related to this topic: nuclear factor erythroid 2 p45-related factor 2, heme oxygenase, neuroblastoma, medulloblastoma, meningioma, astrocytoma, oligodendroglioma, glioblastoma multiforme, and gliomas.

• NRF2
• ROS
• brain cancer
• nuclear factor erythroid 2 p45-related factor 2
• oxidative stress

• Biliverdin
• Cancer
• Carbon monoxide
• Glioblastoma
• Heme oxygenase
• Nrf2
• PUM2

• Nano-immunotherapeutic
• Tumor microenvironmental immune cells-targeted cancer immunotherapy
• Tumor-associated dendritic cell-targeted nano-immunotherapeutics
• Tumor-associated macrophage-targeted nano-immunotherapeutics
• Tumor-infiltrating T cell-targeted nano-immunotherapeutics

• cancer
• chimeric antibody receptor T cells
• immunotherapy
• monoclonal antibodies
• neuroblastoma

Heme oxygenase-1 (HO-1, encoded by HMOX1) through degradation of pro-oxidant heme into carbon monoxide (CO), ferrous ions (Fe²⁺) and biliverdin, exhibits cytoprotective, anti-apoptotic and anti-inflammatory properties. All of these potentially beneficial functions of HO-1 may play an important role in tumors’ development and progression. Moreover, HO-1 is very often upregulated in tumors in comparison to healthy tissues, and its expression is further induced upon chemo-, radio- and photodynamic therapy, what results in decreased effectiveness of the treatment. Consequently, HO-1 can be proposed as a therapeutic target for anticancer treatment in many types of tumors. Nonetheless, possibilities of specific inhibition of HO-1 are strongly limited. Metalloporphyrins are widely used in in vitro studies, however, they are unselective and may exert serious side effects including an increase in HMOX1 mRNA level. On the other hand, detailed information about pharmacokinetics and biodistribution of imidazole-dioxolane derivatives, other potential inhibitors, is lacking. The genetic inhibition of HO-1 by RNA interference (RNAi) or CRISPR/Cas9 approaches provides the possibility to specifically target HO-1; however, the potential therapeutic application of those methods are distant at best. In summary, HO-1 inhibition might be the valuable anticancer approach, however, the ideal strategy for HO-1 targeting requires further studies.

• CRISPR/Cas9
• HO-1 inhibitors
• anticancer strategy
• siRNA
• tumorigenesis

Heme oxygenase-1 (HO-1) can promote tumor growth and reinforce the resistance of diffuse large B-cell lymphoma (DLBCL) cells to chemotherapeutic drug vincristine. We herein found that HO-1 protein expression was higher in high-risk DLBCL patients than in low-risk ones. Silencing HO-1 gene expression resisted vorinostat-induced apoptosis and arrested cell cycle in the G0/G1 phase of LY-10 cells. Western blot, co-immunoprecipitation and chromatin immunoprecipitation assays confirmed that the possible mechanisms may be increased cleaved caspase-3 protein expression, decreased phospho-histone deacetylase 3 protein expression, and activated histone acetylation of P27^Kip1 promoter. Moreover, silencing HO-1 gene expression enhanced vorinostat-induced tumor cell apoptosis, prolonged survival time and promoted P27^Kip1 protein expression in a xenograft mouse model.

In conclusion, HO-1 is a potential therapeutic target of DLBCL. The findings provide a valuable preclinical evidence for sensitizing DLBCL patients with poor prognosis to histone deacetylase inhibitors.

• P27
• diffuse large B-cell lymphoma
• heme oxygenase-1
• histone deacetylase 3
• vorinostat

The upregulation of heme oxygenase-1 (HO-1) is one of the most important mechanisms of cell adaptation to stress. Indeed, the redox sensitive transcription factor Nrf2 is the pivotal regulator of HO-1 induction. Through the antioxidant, antiapoptotic, and antinflammatory properties of its metabolic products, HO-1 plays a key role in healthy cells in maintaining redox homeostasis and in preventing carcinogenesis. Nevertheless, several lines of evidence have highlighted the role of HO-1 in cancer progression and its expression correlates with tumor growth, aggressiveness, metastatic and angiogenetic potential, resistance to therapy, tumor escape, and poor prognosis, even though a tumor- and tissue-specific activity has been observed. In this review, we summarize the current literature regarding the pro-tumorigenic role of HO-1 dependent tumor progression as a promising target in anticancer strategy.

• HO-1
• NK
• NSCLC
• Nrf2
• cancer progression
• immune-escape
• melanoma
• oxidative stress
• prostate cancer
• tumor microenvironment

To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide (HO/CO) pathway in the constipating effects of granisetron.

For in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous (sc)], zinc protoporphyrin IX [ZnPPIX, 50 μg/kg/intraperitoneal (ip)] and hemin (50 μmol/L/kg/ip), alone or in combination. For in vitro studies, the contractile neurogenic response to electrical field stimulation (EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine (ACh, 0.1-100 μmol/L) were evaluated on colon specimens incubated with granisetron (3 μmol/L, 15 min), ZnPPIX (10 μmol/L, 60 min) or CO-releasing molecule-3 (CORM-3, 100, 200, 400 μmol/L) alone or in combination. These experiments were performed under co-treatment with or without atropine (3 μmol/L, a muscarinic receptor antagonist) or N^G-nitro-L-Arginine (L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor).

Administration of granisetron (50, 75 μg/kg) in vivo significantly increased the time to first defecation (P = 0.045 vs vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of ZnPPIX or hemin alone had no effect on this gastrointestinal motility parameter, ZnPPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered in vitro, granisetron alone (3 μmol/L) did not significantly modify the colon’s contractile response to either EFS or ACh. Incubation with ZnPPIX alone (10 μmol/L) significantly reduced the colon’s contractile response to EFS (P = 0.016) but had no effect on contractile response to ACh. Co-administration of ZnPPIX and atropine (3 μmol/L) abolished the ZnPPIX-mediated decrease in contractile response to EFS. Conversely, incubation with CORM-3 (400 μmol/L) alone increased both the contractile response to EFS at 10 Hz (10 Hz: 71.02 ± 19.16 vs 116.25 ± 53.70, P = 0.01) and the contractile response to ACh (100 μmol/L) (P = 0.012). Co-administration of atropine abolished the CORM-3-mediated effects on the EFS-mediated response. When granisetron was co-incubated in vitro with ZnPPIX, the ZnPPIX-mediated decrease in colon contractile response to EFS was lost. On the other hand, co-incubation of granisetron and CORM-3 (400 μmol/L) further increased the colon’s contractile response to EFS (at 5 Hz: P = 0.007; at 10 Hz: P = 0.001) and to ACh (ACh 10 μmol/L: P = 0.001; ACh 100 μmol/L: P = 0.001) elicited by CORM-3 alone. L-NNA co-administered with granisetron and CORM-3 abolished the potentiating effect of CORM-3 on granisetron on both the EFS-induced and ACh-induced contractile response.

Taken together, findings from in vivo and in vitro studies suggest that the HO/CO pathway is involved in the constipating effects of granisetron.

• Granisetron
• Carbon monoxide
• Heme oxygenase
• Colon
• Contraction
• Neurogenic response
• Myogenic response

• Acetylcholine/pharmacology
• Animals
• Carbon Monoxide/metabolism
• Colon/drug effects
• Colon/metabolism
• Colon/physiopathology
• Constipation/chemically induced
• Constipation/metabolism
• Constipation/physiopathology
• Constipation/prevention & control
• Defecation/drug effects
• Dose-Response Relationship, Drug
• Electric Stimulation
• Gastrointestinal Motility/drug effects
• Granisetron/toxicity
• Heme Oxygenase (Decyclizing)/metabolism
• Hemin/pharmacology
• In Vitro Techniques
• Male
• Organometallic Compounds/pharmacology
• Protoporphyrins/pharmacology
• Rats, Sprague-Dawley
• Serotonin Antagonists/toxicity
• Time Factors