Search Results (21)

The sustainable production of carbon-free fuels such as hydrogen is an important goal in the search for alternative energy sources. Herein, we report a peptide-based system for light-driven hydrogen evolution from water under neutral conditions. The M1 peptide is an ABC triblock polymer featuring two coiled-coil alpha-helical regions flanking a water-soluble, polyanionic, intrinsically disordered region. M1 formed a hydrogel at high concentrations upon binding to cobalt protoporphyrin IX. This process is driven by the terminal regions, which coordinate the metalloporphyrin through histidine residues and form helical oligomers interconnected by flexible, intrinsically disordered regions, resulting in network formation. Co-M1 catalyzes hydrogen production upon irradiation in the presence of a photosensitizer and a sacrificial electron donor; the activity of Co-M1 is eight times higher than that of free Co-PPIX. Full article

Metalloporphyrins (MPs) that induce heme oxygenase (HO)-1 were shown to attenuate complement-mediated glomerular injury, with cobalt protoporphyrin IX (CoPPIX) being the most effective. To decipher the efficacy between CoPPIX and its constituents (Co, PPIX), we compared the outcomes of treatment with each in a rat model of complement-dependent immune injury of glomerular epithelial cells (podocytes). Outcomes were correlated with HO-1 induction and expression levels of complement C3 and of the complement activation regulators (CARs) cluster of differentiation (CD)55, CD59, and CR1-related gene y protein product (Crry). Podocyte injury was induced in rats following a single injection of the complement-fixing antibody against the podocyte antigen, Fx1A. CoPPIX or its constituents, cobaltous chloride (CoCl₂) and protoporphyrin IX (PPIX), were injected prior to and on alternate days thereafter. Urine was assessed for protein excretion and kidney cortex samples were processed for histopathology and assessment of target gene mRNA and protein levels using digital polymerase Chain Reaction (dPCR) and capillary-based Western blot analysis. The anti-Fx1A antibody caused proteinuria and podocyte injury. Treatment with the full CoPPIX chelate reduced proteinuria but treatment with either CoCl₂ or PPIX did not. CoPPIX treatment potently induced HO-1 and reduced tissue C3 mRNA and protein levels. It also increased CD55, CD59, and Crry mRNA, with an inconsistent effect on protein levels. The Co moiety was required for HO-1 induction but not for the decrease in C3. This decrease did not significantly correlate with the effects of CoPPIX treatment on CD55 protein levels. Chelation of cobalt to PPIX enhanced its potency to induce HO-1 but reduced that on CD55 induction. These observations distinguish between the effects of CoPPIX and its constituents on proteinuria consequent to complement-mediated podocyte injury and underlying mediators and identify this MP as a potential disease-modifying agent. Full article

Iron is a trace element that is indispensable for the growth and development of animals. Excessive iron supplementation may lead to iron overload and elevated reactive oxygen species (ROS) production in animals, causing cellular damage. Nevertheless, the precise mechanism by which iron overload causes cell injury remains to be fully elucidated. In this study, 16 male SD rats aged 6 to 7 weeks were randomly assigned to either a control group (CON) or an iron overload group (IO). Rats in the iron overload group received 150 mg/kg iron dextran injections every three days for a duration of four weeks. The results indicated that iron treatment with iron dextran significantly increased the scores of steatosis (p < 0.05) and inflammation (p < 0.05) in the NAS score. The integrated transcriptomic and proteomic analysis suggests that HO-1 and Lnc286.2 are potentially significant in iron overload-induced liver injury in rats. In vitro experiments utilizing ferric ammonium citrate (FAC) were conducted to establish an iron overload model in rat liver-derived BRL-3A cells. The result found that FAC treatment can significantly increase the BRL-3A cell’s Fe²⁺ content (p < 0.05), ROS (p < 0.01), lipid ROS (p < 0.01) levels, and the expression of the HO-1 gene and protein (p < 0.01), aligning with proteomic and transcriptomic findings. HO-1 inhibition can significantly decrease BRL-3A cell vitality (p < 0.01) and promote ROS (p < 0.05) and lipid ROS (p < 0.01), thus aggravating FAC-induced BRL-3A cell iron overload damage. Using the agonist of HO-1 agonist cobalt protoporphyrin (CoPP) to induce HO-1 overexpression can significantly alleviate the decrease in FAC-induced BRL-3A cell viability (p < 0.01), ROS (p < 0.01), and lipid ROS (p < 0.01). In addition, siLnc286.2 treatment can increase HO-1 expression, alleviate the decline of FAC-induced BRL-3A cell activity, and increase lipid ROS (p < 0.05) content. In conclusion, the findings of this study suggest that by suppressing the expression of Lnc286.2, we can enhance the expression of HO-1, which in turn alleviates lipid peroxidation in cells and increases their antioxidant capacity, thereby exerting a protective effect against liver cell injury induced by iron overload. Full article

Diabetic retinopathy is characterized by hyperglycemic retinal pigment epithelial cells that secrete excessive pro-inflammatory cytokines and VEGF, leading to retinal damage and vision loss. Cobalt protoporphyrin (CoPP) is a compound that can reduce inflammatory responses by inducing high levels of HO-1. In the present study, the therapeutic effects of CoPP were examined in ARPE-19 cells under hyperglycemia. ARPE-19 cells were incubated in culture media containing either 5.5 mM (NG) or 25 mM (HG) glucose, with or without the addition of 0.1 µM CoPP. Protein expressions in samples were determined by either Western blotting or immunostaining. A Seahorse metabolic analyzer was used to assess the impact of CoPP treatment on mitochondrial respiration in ARPE-19 cells in NG or HG media. ARPE-19 cells cultured in NG media displayed different cell morphology than those cultured in HG media. CoPP treatment induced high HO-1 expressions and significantly enhanced the viability of ARPE-19 cells under hyperglycemia. Moreover, CoPP significantly downregulated expressions of inflammatory and apoptotic markers and significantly upregulated mitochondrial respiration in APRPE-19 cells under hyperglycemia. CoPP treatment significantly enhanced cell viability in ARPE-19 cells under hyperglycemia. The treatment also downregulated the expressions of pro-inflammatory and upregulated mitochondrial respiration in the hyperglycemic cells. Full article

Chemotherapy-provoked peripheral neuropathy and its associated affective disorders are important adverse effects in cancer patients, and its treatment is not completely resolved. A recent study reveals a positive interaction between molecular hydrogen (H₂) and a heme oxygenase (HO-1) enzyme inducer, cobalt protoporphyrin IX (CoPP), in the inhibition of neuropathic pain provoked by nerve injury. Nevertheless, the efficacy of CoPP co-administered with hydrogen-rich water (HRW) on the allodynia and emotional disorders related to paclitaxel (PTX) administration has not yet been assessed. Using male C57BL/6 mice injected with PTX, we examined the effects of the co-administration of low doses of CoPP and HRW on mechanical and thermal allodynia and anxiodepressive-like behaviors triggered by PTX. Moreover, the impact of this combined treatment on the oxidative stress and inflammation caused by PTX in the amygdala (AMG) and dorsal root ganglia (DRG) were studied. Our results indicated that the antiallodynic actions of the co-administration of CoPP plus HRW are more rapid and higher than those given by each of them when independently administered. This combination inhibited anxiodepressive-like behaviors, the up-regulation of the inflammasome NLRP3 and 4-hydroxynonenal, as well as the high mRNA levels of some inflammatory mediators. This combination also increased the expression of NRF2, HO-1, superoxide dismutase 1, glutathione S-transferase mu 1, and/or the glutamate-cysteine ligase modifier subunit and decreased the protein levels of BACH1 in the DRG and/or AMG. Thus, it shows a positive interaction among HO-1 and H₂ systems in controlling PTX-induced neuropathy by modulating inflammation and activating the antioxidant system. This study recommends the co-administration of CoPP plus HRW as an effective treatment for PTX-provoked neuropathy and its linked emotive deficits. Full article

Equid alphaherpesvirus type 8 (EqHV-8) is the causative agent of severe respiratory disease, abortions, and neurological syndromes in equines and has resulted in huge economic losses to the donkey industry. Currently, there exist no therapeutic molecules for controlling EqHV-8 infection. We evaluated the potential antiviral activity of cobalt protoporphyrin (CoPP) against EqHV-8 infection. Our results demonstrated that CoPP inhibited EqHV-8 infection in susceptible cells and mouse models. Furthermore, CoPP blocked the replication of EqHV-8 via HO-1 (heme oxygenase-1) mediated type I interferon (IFN) response. In conclusion, our data suggested that CoPP could serve as a novel potential molecule to develop an effective therapeutic strategy for EqHV-8 prevention and control. Full article

Depending on their central metal atom, metalloporphyrins (MPs) can attenuate or exacerbate the severity of immune-mediated kidney injury, and this has been attributed to the induction or inhibition of heme oxygenase (HO) activity, particularly the inducible isoform (HO-1) of this enzyme. The role of central metal or porphyrin moieties in determining the efficacy of MPs to attenuate injury, as well as mechanisms underlying this effect, have not been assessed. Using an antibody-mediated complement-dependent model of injury directed against rat visceral glomerular epithelial cells (podocytes) and two MPs (FePPIX, CoPPIX) that induce both HO-1 expression and HO enzymatic activity in vivo but differ in their chelated metal, we assessed their efficacy in reducing albuminuria. Podocyte injury was induced using rabbit immune serum raised against the rat podocyte antigen, Fx1A, and containing an anti-Fx1A antibody that activates complement at sites of binding. FePPIX or CoPPIX were injected intraperitoneally (5 mg/kg) 24 h before administration of the anti-Fx1A serum and on days 1, 3, 6, and 10 thereafter. Upon completion of urine collection on day 14, the kidney cortex was obtained for histopathology and isolation of glomeruli, from which total protein extracts were obtained. Target proteins were analyzed by capillary-based separation and immunodetection (Western blot analysis). Both MPs had comparable efficacy in reducing albuminuria in males, but the efficacy of CoPPIX was superior in female rats. The metal-free protoporphyrin, PPIX, had minimal or no effect on urine albumin excretion. CoPPIX was also the most potent MP in inducing glomerular HO-1, reducing complement deposition, and preserving the expression of the complement regulatory protein (CRP) CD55 but not that of CD59, the expression of which was reduced by both MPs. These observations demonstrate that the metal moiety of HO-1-inducing MPs plays an important role in reducing proteinuria via mechanisms involving reduced complement deposition and independently of an effect on CRPs. Full article

This study explores the electrochemical reduction in CO₂ using room temperature ionic liquids as solvents or electrolytes, which can minimize the environmental impact of CO₂ emissions. To design effective CO₂ electrochemical systems, it is crucial to identify intermediate surface species and reaction products in situ. The study investigates the electrochemical reduction in CO₂ using a cobalt porphyrin molecular immobilized electrode in 1-n-butyl-3-methyl imidazolium tetrafluoroborate (BMI.BF4) room temperature ionic liquids, through in-situ surface-enhanced Raman spectroscopy (SERS) and electrochemical technique. The results show that the highest faradaic efficiency of CO produced from the electrochemical reduction in CO₂ can reach 98%. With the potential getting more negative, the faradaic efficiency of CO decreases while H₂ is produced as a competitive product. Besides, water protonates porphyrin macrocycle, producing pholorin as the key intermediate for the hydrogen evolution reaction, leading to the out-of-plane mode of the porphyrin molecule. Absorption of CO₂ by the ionic liquids leads to the formation of BMI·CO₂ adduct in BMI·BF₄ solution, causing vibration modes at 1100, 1457, and 1509 cm⁻¹. However, the key intermediate of ${\mathrm{CO}}_2^{-}·$ radical is not observed. The υ(CO) stretching mode of absorbed CO is affected by the electrochemical Stark effect, typical of CO chemisorbed on a top site. Full article

Vitamins are essential for sustaining daily activities and perform crucial roles in metabolism, such as preventing vascular events and delaying the development of diabetic nephropathy. The ultrasensitive assessment of thiamine in foods is required for food quality evaluation. A mini-platform utilizing two 3D sensors based on nanographene and gold nanoparticles paste modified with protoporphyrin IX and protoporphyrin IX cobalt chloride is proposed for the detection of thiamine in blueberry syrup, multivitamin tablets, water, and a biological sample (urine). Differential pulse voltammetry was utilized for the characterization and validation of the suggested sensors. The sensor modified with protoporphyrin IX has a detection limit of 3.0 × 10⁻¹³ mol L⁻¹ and a quantification limit of 1.0 × 10⁻¹² mol L⁻¹, whereas the sensor modified with protoporphyrin IX cobalt chloride has detection and quantification limits of 3.0 × 10⁻¹² and 1.0 × 10⁻¹¹ mol L⁻¹, respectively. High recoveries (values greater than 95.00%) and low RSD (%) values (less than 5.00%) are recorded for both 3D sensors when used for the determination of thiamine in blueberry syrup, multivitamin tablets, water, and urine, demonstrating the 3D sensors’ and suggested method’s high reliability. Full article

A relationship between carbon monoxide (CO) and hydrogen sulfide (H₂S) has been described in different pathological conditions, but their interaction in modulating joint pain has not yet been investigated. In young female mice with monosodium acetate-induced joint degeneration and pain, we assessed: (1) the effects of CORM-2 (tricarbonyldichlororuthenium(II)dimer), a CO-releasing molecule, and CoPP (cobalt protoporphyrin IX), an inducer of heme oxygenase 1 (HO-1), administered alone and combined with low doses of two slow-releasing H₂S donors, DADS (diallyl disulfide) and GYY4137 (morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex) on the mechanical allodynia and loss of grip strength provoked by joint degeneration; (2) the role of Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1) and HO-1 in the antinociceptive actions of H₂S donors; (3) the impact of DADS and GYY4137 treatment on the expression of Nrf2 and several antioxidant proteins in dorsal root ganglia (DRG) and periaqueductal gray matter (PAG). Our data showed that treatment with H₂S donors inhibited allodynia and functional deficits, while CORM-2 and CoPP only prevented allodynia. The Nrf2 pathway is implicated in the analgesic actions of DADS and GYY4137 during joint degeneration. Moreover, the co-administration of low doses of CORM-2 or CoPP with DADS or GYY4137 produced higher antiallodynic effects and greater recovery of grip strength deficits than those produced by each of these compounds alone. The activation of the antioxidant system caused by H₂S donors in DRG and/or PAG might explain the enhancement of antinociceptive effects. These data reveal a positive interaction between H₂S and CO in modulating joint pain in female mice. Full article

An important virulence trait of Salmonella enterica serovar Typhimurium (S. Typhimurium) is the ability to avoid the host immune response, generating systemic and persistent infections. Host cells play a crucial role in bacterial clearance by expressing the enzyme heme oxygenase 1 (Hmox1), which catalyzes the degradation of heme groups into Fe²⁺, biliverdin, and carbon monoxide (CO). The role of Hmox1 activity during S. Typhimurium infection is not clear and previous studies have shown contradictory results. We evaluated the effect of pharmacologic modulation of Hmox1 in a mouse model of acute and persistent S. Typhimurium infection by administering the Hmox1 activity inductor cobalt protoporphyrin-IX (CoPP) or inhibitor tin protoporphyrin-IX (SnPP) before infection. To evaluate the molecular mechanism involved, we measured the colocalization of S. Typhimurium and autophagosome and lysosomal markers in macrophages. Administering CoPP reduced the bacterial burden in organs of mice 5 days post-infection, while SnPP-treated mice showed bacterial loads similar to vehicle-treated mice. Furthermore, CoPP reduced bacterial loads when administered after infection in macrophages in vitro and in a persistent infection model of S. Typhimurium in vivo, while tin protoporphyrin-IX (SnPP) treatment resulted in a bacterial burden similar to vehicle-treated controls. However, we did not observe significant differences in co-localization of green fluorescent protein (GFP)-labeled S. Typhimurium with the autophagic vesicles marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the lysosomal marker lysosomal-associated membrane protein 1 (LAMP-1) in macrophages treated with CoPP. Our results suggest that CoPP can enhance antimicrobial activity in response to Salmonella infection, reducing bacterial dissemination and persistence in mice, in a CO and autophagy- independent manner. Full article

Chemotherapy-induced peripheral neuropathy constitutes an unresolved clinical problem that severely decreases the quality of the patient’s life. It is characterized by somatosensory alterations, including chronic pain, and a high risk of suffering mental disorders such as depression and anxiety. Unfortunately, an effective treatment for this neuropathology is yet to be found. We investigated the therapeutic potential of cobalt protoporphyrin IX (CoPP), a heme oxygenase 1 inducer, and morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex (GYY4137), a slow hydrogen sulfide (H₂S) donor, in a preclinical model of paclitaxel (PTX)-induced peripheral neuropathy (PIPN) in mice. At three weeks after PTX injection, we evaluated the effects of the repetitive administration of 5 mg/kg of CoPP and 35 mg/kg of GYY4137 on PTX-induced nociceptive symptoms (mechanical and cold allodynia) and on the associated emotional disturbances (anxiety- and depressive-like behaviors). We also studied the mechanisms that could mediate their therapeutic properties by evaluating the expression of key proteins implicated in the development of nociception, oxidative stress, microglial activation, and apoptosis in prefrontal cortex (PFC) and dorsal root ganglia (DRG) of mice with PIPN. Results demonstrate that CoPP and GYY4137 treatments inhibited both the nociceptive symptomatology and the derived emotional alterations. These actions were mainly mediated through potentiation of antioxidant responses and inhibiting oxidative stress in the DRG and/or PFC of mice with PIPN. Both treatments normalized some plasticity changes and apoptotic reactions, and GYY4137 blocked microglial activation induced by PTX in PFC. In conclusion, this study proposes CoPP and GYY4137 as good candidates for treating neuropathic pain, anxiety- and depressive-like effects of PTX. Full article

This study hypothesizes that bacteria inhabiting shale rock affect the content of the sedimentary cobalt protoporphyrin present in it and can use it as a precursor for heme synthesis. To verify this hypothesis, we conducted qualitative and quantitative comparative analyses of cobalt protoporphyrin as well as heme, and heme iron in shale rock that were (i) inhabited by bacteria in the field, (ii) treated with bacteria in the laboratory, and with (iii) bacterial culture on synthetic cobalt protoporphyrin. Additionally, we examined the above-mentioned samples for the presence of enzymes involved in the heme biosynthesis and uptake as well as hemoproteins. We found depletion of cobalt protoporphyrin and a much higher heme concentration in the shale rock inhabited by bacteria in the field as well as the shale rock treated with bacteria in the laboratory. Similarly, we observed the accumulation of protoporphyrin in bacterial cells grown on synthetic cobalt protoporphyrin. We detected numerous hemoproteins in metaproteome of bacteria inhabited shale rock in the field and in proteomes of bacteria inhabited shale rock and synthetic cobalt protoporhyrin in the laboratory, but none of them had all the enzymes involved in the heme biosynthesis. However, proteins responsible for heme uptake, ferrochelatase and sirohydrochlorin cobaltochelatase/sirohydrochlorin cobalt-lyase were detected in all studied samples. Full article

Cholestatic liver diseases can progress to end-stage liver disease and reduce patients’ quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that displays antioxidant action. It has been found that this enzyme plays a protective role against various inflammatory diseases. However, the role of HO-1 in cholestatic liver diseases has not yet been investigated. Here, we examined whether pharmacological induction of HO-1 by cobalt protoporphyrin (CoPP) ameliorates cholestatic liver injury. To this end, a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding was used. Administration of CoPP ameliorated liver damage and cholestasis with HO-1 upregulation in DDC diet-fed mice. Induction of HO-1 by CoPP suppressed the DDC diet-induced oxidative stress and hepatocyte apoptosis. In addition, CoPP attenuated cytokine production and inflammatory cell infiltration. Furthermore, deposition of the extracellular matrix and expression of fibrosis-related genes after DDC feeding were also decreased by CoPP. HO-1 induction decreased the number of myofibroblasts and inhibited the transforming growth factor-β pathway. Altogether, these data suggest that the pharmacological induction of HO-1 ameliorates cholestatic liver disease by suppressing oxidative stress, hepatocyte apoptosis, and inflammation. Full article

Nuclear receptor REV-ERBβ is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBβ to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluorescence imaging agent. The replacement of iron with cobalt as the metal center of protoporphyrin IX changes the ligand from an agonist to an antagonist of REV-ERBβ. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERBβ in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic simulations to compare the effects of REV-ERBβ binding to Heme and CoPP, respectively. The initial poses of Heme and CoPP in complex with agonist and antagonist forms of REV-ERBβ were predicted using molecular docking. The binding energies of each ligand were calculated using the MM/PBSA method. The computed binding affinity of Heme to REV-ERBβ was stronger than that of CoPP, in agreement with experimental results. CoPP altered the conformation of the ligand-binding site of REV-ERBβ, disrupting the binding site for nuclear receptor corepressor, which is required for REV-ERBβ to regulate the transcription of downstream target genes. Those results suggest that a subtle change in the metal center of porphyrin can change the behavior of porphyrin in cancer cell signaling. Therefore, modification of porphyrin-based agents for cancer therapy should be conducted carefully to avoid triggering unfavorable effects. Full article