Hydralazine Research Articles

Hydralazine and Hydrazine Derivatives: Properties, Applications, and Repositioning Potential.

The investigation of new drugs is slow and costly. Drug repositioning, like with Hydralazine (HDZ), an old antihypertensive, can accelerate the process. HDZ and its hydrazonic derivatives exhibit diverse biological activities, promising for new drugs. This review explores HDZ's repositioning potential and its derivatives' applications in various biological activities. It identified 70 relevant articles through database searches. HDZ shows potential in neurology, oncology, nephrology, and gynecology, with clinical trials up to Phase III. Hydralazine-valproate, marketed in Mexico, proves effective in combination with chemotherapy. Hydrazonic derivatives offer broad applications in medicine. Studying their structure-activity relationship can enhance efficacy. This review summarizes their properties and pharmacological activities succinctly.

LC-ESI-MS/MS methods for the quantification of hydrazine mono lactose adduct and hydrazine di lactose adduct in isosorbide dinitrate and hydralazine hydrochloride tablets

Isosorbide dinitrate and hydralazine hydrochloride tablets treat heart failure in addition to conventional therapy, prolong hospitalization for heart failure, and enhance patient-reported functional status. LC-MS/MS methods developed and validated separately for the quantification of hydrazine mono-lactose adduct and hydrazine di-lactose adduct impurities in the isosorbide and hydralazine hydrochloride tablets. Separation of hydrazine mono-lactose adduct impurity achieved on ZIC-HILIC (100 × 4.6 mm, 5 µm) column with 0.1% formic acid in water as mobile phase A and acetonitrile as mobile phase B. The HPLC method gradient elution is; Tmin/% of B: 0/90, 15/40, 15.1/90, and 20/90. The flow rate is 1.0 mL per minute, and the injection volume is 20 µL. Separation of hydrazine di-lactose adduct impurity achieved on Inertsil HILIC (150 × 4.6 mm, 5 µm) column with 10 Mm ammonium acetate in water as mobile phase A and acetonitrile as mobile phase B. The HPLC method gradient elution is; Tmin/% of B: 0/90, 15/40, 15.1/90, and 18/90. The flow rate is 1.0 mL per minute, and the injection volume is 40 µL. Method validation has demonstrated both methods are specific, sensitive, linear, precise, accurate, stable and robust.

Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin.

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.

Smart Nanoassembly Enabling Activatable NIR Fluorescence and ROS Generation with Enhanced Tumor Penetration for Imaging-Guided Photodynamic Therapy.

Fluorescence imaging-guided photodynamic therapy (FIG-PDT) holds promise for cancer treatment, yet challenges persist in poor imaging quality, phototoxicity, and insufficient anti-tumor effect. Herein, a novel nanoplatform, LipoHPM, designed to address these challenges, is reported. This approach employs an acid-sensitive amine linker to connect a biotin-modified hydrophilic polymer (BiotinPEG) with a new hydrophobic photosensitizer (MBA), forming OFF-state BiotinPEG-MBA (PM) micelles via an aggregation-caused quenching (ACQ) effect. These micelles are then co-loaded with the tumor penetration enhancer hydralazine (HDZ) into pH-sensitive liposomes (LipoHPM). Leveraging the ACQ effect, LipoHPM is silent in both fluorescence and reactive oxygen species (ROS) generation during blood circulation but restores both properties upon disassembly. Following intravenous injection in tumor-bearing mice, LipoHPM actively targets tumor cells overexpressing biotin-receptors, contributing to enhanced tumor accumulation. Upon cellular internalization, LipoHPM disassembles within lysosomes, releasing HDZ to enhance tumor penetration and inhibit tumor metastasis. Concurrently, the micelles activate fluorescence for tumor imaging and boost the production of both type-I and type-II ROS for tumor eradication. Therefore, the smart LipoHPM synergistically integrates near-infrared emission, activatable tumor imaging, robust ROS generation, efficient anti-tumor and anti-metastasis activity, successfully overcoming limitations of conventional photosensitizers and establishing itself as a promising nanoplatform for potent FIG-PDT applications.

Neuroprotection by acrolein sequestration through exogenously applied scavengers and endogenous enzymatic enabling strategies in mouse EAE model

We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in MS pathology. In this study, we found that the acrolein scavenger hydralazine (HZ), when applied from the day of induction, can suppress acrolein and alleviate motor and sensory deficits in a mouse experimental autoimmune encephalomyelitis (EAE) model. Furthermore, we also demonstrated that HZ can alleviate motor deficits when applied after the emergence of MS symptoms, making potential anti-acrolein treatment a more clinically relevant strategy. In addition, HZ can reduce both acrolein and MPO, suggesting a connection between acrolein and inflammation. We also found that in addition to HZ, phenelzine (PZ), a structurally distinct acrolein scavenger, can mitigate motor deficits in EAE when applied from the day of induction. This suggests that the likely chief factor of neuroprotection offered by these two structurally distinct acrolein scavengers in EAE is their common feature of acrolein neutralization. Finally, up-and-down regulation of the function of aldehyde dehydrogenase 2 (ALDH2) in EAE mice using either a pharmacological or genetic strategy led to correspondent motor and sensory changes. This data indicates a potential key role of ALDH2 in influencing acrolein levels, oxidative stress, inflammation, and behavior in EAE. These findings further consolidate the critical role of aldehydes in the pathology of EAE and its mechanisms of regulation. This is expected to reinforce and expand the possible therapeutic targets of anti-aldehyde treatment to achieve neuroprotection through both endogenous and exogenous manners.

A novel electrochemical strategy using a newly developed carbon-based sensor for the detection of antihypertensive drug: Hydralazine hydrochloride

Hydralazine hydrochloride (HZH) is a popular nonsteroidal anti-inflammatory vasodilator. HZH was explored using Zirconium-doped ZnO nanoparticles drop-casted on a β-cyclodextrin (β-CDX) modified carbon paste electrode (Zr:ZnO/β-CDX@CPE). X-ray diffraction (XRD) and scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDX) were used to characterize the sample. Electrochemical impedance spectroscopy (EIS) assessed material performance. HZH was tested under different phosphate buffer conditions using Cyclic voltammetry (CV) and square wave voltammetry (SWV). Results were best at pH 7.0 in the potential range of −0.4 V to 0.7 V. The diffusion electrode technique was utilized to study the effects of different factors on the electrochemical characteristics. Quantitative evaluation of HZH was performed using SWV in the concentration range of 0.8–20 μM, showing linearity. The limit of detection (LOD) and limit of quantification (LOQ) were determined as 4.8 × 10−9 M and 16.2 × 10−9 M, respectively. This innovative technique was successfully applied to measure HZH in biological and water samples.

Method Verification and Validation of Hydralazine Hydrochloride: Spectrophotometric Analysis in Pure and Pharmaceutical Formulations

Method Verification and Validation of Hydralazine Hydrochloride: Spectrophotometric Analysis in Pure and Pharmaceutical Formulations

In vivo ameliorative effects of vitamin E against hydralazine-induced lupus

ObjectiveIn this study, we investigated the in vivo ameliorative effects of vitamin E in a hydralazine-induced lupus model, which closely resembles SLE in humans. We aim to shed light on...

Fundamentals for the repurposing of hydralazine as an anti-neoplastic drug

Hydralazine (HDZ) is a drug patented in 1949 that has been used for the treatment of arterial hypertension since 1953. New and better anti-hypertensive drugs have almost moved HDZ into oblivion. Interestingly, anti-cancer effects were found and this drug is seriously being considered for repurposing it for cancer treatment. The main mechanism of action against tumors seems to be its ability to act as a demethylator agent. By demethylating the promoter region of tumor suppressor genes HDZ seems to restore the effects of these genes, which are frequently inhibited in cancer through epigenetic mechanisms. However, HDZ also has some other important involved mechanisms such as anti-angiogenesis, and reversal of resistance to imatinib. Particularly important is its ability to restore the activity of non-mutated p16 in cancer. HDZ ability to inhibit glutamate oxaloacetate transaminase 1 is a recent finding that will probably add further interest to the drug in cancer treatment. This review analyzes the anti-tumoral effects of HDZ.

Hydralazine represses Fpn ubiquitination to rescue injured neurons via competitive binding to UBA52

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

Utilization of hydralazine as a reactive matrix for enhanced detection and on-MALDI-target derivatization of saccharides

Saccharides are a sort of ubiquitous and vital molecules within the whole life. However, the application of saccharides analysis with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is restricted by their low ionization efficiency and the instability of the sialic acid fraction. Derivatization strategy based on nonreductive amination provides a good solution, however, this is often time consuming and may result in sample loss due to removal of excessive derivatization reagents. Herein, hydralazine (HZN) was utilized as a reactive matrix for labeling reducing saccharides directly on MALDI target which eliminated tedious sample preparation and avoided sample loss. After optimization, effective and reproducible on-MALDI-target derivatization of neutral and acidic saccharides was achieved in both positive and negative modes. Compared with 2,5-dihydroxybenzoic acid (DHB) and 9-aminoacridine (9-AA), HZN improved the detection sensitivity of reducing saccharides and provided more abundant fragment ions in MS/MS analysis. Moreover, 26 kinds of neutral glycans and 5 kinds of sialic glycans were identified from ovalbumin (OVA) and bovine fetuin, respectively. Combined with the statistical models, this strategy could be used to distinguish and predict samples of 6 brands of beer, and discriminate 2 kinds of beer fermentation modes. In addition, HZN was applied for quantitative analysis of glucose in urine samples, and the obtained urine glucose concentrations of diabetic patients were consistent with the clinical test results, showing the potential of qualitative and quantitative analysis of reducing saccharides in complex samples.

Synergistic effect of hydralazine associated with triazoles on Candida spp. in planktonic cells.

Objective: To evaluate the antifungal activity of hydralazine hydrochloride alone and in synergy with azoles against Candida spp. and the action mechanism. Methods: We used broth microdilution assays to determine the MIC, checkerboard assays to investigate synergism, and flow cytometry and molecular docking tests to ascertain action mechanism. Results: Hydralazine alone had antifungal activity in the range of 16-128μg/ml and synergistic effect with itraconazole versus 100% of the fungal isolates, while there was synergy with fluconazole against 11.11% of the isolates. There was molecular interaction with the receptors exo-B(1,3)-glucanase and CYP51, causing reduced cell viability and DNA damage. Conclusion: Hydralazine is synergistic with itraconazole and triggers cell death of Candida spp. at low concentrations, demonstrating antifungal potential.

The free hydralazine anti-hypertensive drug and new salts with improved solubility

Although long used as an antihypertensive drug because of its vasodilator properties, Hydralazine (HDZ) has received renewed attention in the last few years due to its secondary therapeutic effects, which has led to its repurposing for its antioxidative, anti-apoptotic, and anti-inflammatory abilities, especially in cardiovascular and renal diseases. Given the worldwide prevalence of these diseases and that only the hydrochloride salt form of this drug has been reported and commercialized until now, in this paper we describe the synthesis, crystalline structure and physicochemical properties of the free hydralazine and its two new salts, a bromide (HDZ-Br) and a nitrate (HDZ-NO3), aiming to provide new candidates of HDZ solid forms that can be potentially used as an alternative to the pattern antihypertensive treatment, with better properties than the commercial one and can also be used in new applications addressed to this drug. Herein we investigated the three new multicomponent solid forms using single crystal X-ray diffraction (SCXRD), X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA), Infrared/Raman spectroscopies, and relative solubility studies. Interestingly, all structures showed the formation of HDZ columns intercalated with ions columns as well as a strong tendency to develop π···π stacking interactions among HDZ molecules which can be useful for future design of new potential multicomponent forms of HDZ. The new reported salts show a relative solubility higher than the commercially hydralazine hydrochloride form, suggesting that they can be potentially useful in new pharmaceutical formulations.

Identification and structural characterization of lactose adduct impurities in isosorbide dinitrate and hydralazine hydrochloride tablets by liquid chromatography‐mass spectrometry and nuclear magnetic resonance studies

AbstractIsosorbide dinitrate and hydralazine hydrochloride tablets are approved for the treatment of heart failure, prolonged hospitalization for heart failure, and enhanced patient‐reported functional status. It has been administered orally. Isosorbide dinitrate and hydralazine hydrochloride tablets contained two additional major unknown peaks (Degradation Product 1 and Degradation Product 2) in the stability studies (25°C/60% relative humidity and 40°C/75% relative humidity). These two unknown degradation peaks formed due to the heat (thermal) and humidity stress of hydralazine hydrochloride. Liquid chromatography separated these unknown degradant peaks. Initially, liquid chromatography‐mass spectrometry assessed the degradation pathways and mass of two degradants. Afterward, preparative‐liquid chromatography isolated the two major unknown degradation impurities formed under heat (thermal) and humidity stress conditions. Further, to confirm the structures, nuclear magnetic resonance spectroscopy evaluated these two degradants. The liquid chromatography‐mass spectrometry and nuclear magnetic resonance spectral data confirmed that the two degradation impurities are hydralazine lactosone ring‐opened adduct (Degradation Product 1) and s‐triazolo [3,4‐α] phthalazine (Degradation Product 2).

Cell-type dependent regulation of pluripotency and chromatin remodeling genes by hydralazine

BackgroundThe generation of induced pluripotent stem cells has opened the field of study for stem cell research, disease modeling and drug development. However, the epigenetic signatures present in somatic cells make cell reprogramming still an inefficient process. This epigenetic memory constitutes an obstacle in cellular reprogramming. Here, we report the effect of hydralazine (HYD) and valproic acid (VPA), two small molecules with proven epigenetic activity, on the expression of pluripotency genes in adult (aHF) and neonatal (nbHF) human fibroblasts.MethodsaHF and nbHF were treated with HYD and/or VPA, and viability and gene expression assays for OCT4, NANOG, c-MYC, KLF4, DNMT1, TET3, ARID1A and ARID2 by quantitative PCR were performed. aHF and nbHF were transfected with episomal plasmid bearing Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and exposed to HYD and VPA to determine the reprogramming efficiency. Methylation sensitive restriction enzyme (MSRE) qPCR assays were performed on OCT4 and NANOG promoter regions. Immunofluorescence assays were carried out for pluripotency genes on iPSC derived from aHF and nbHF.ResultsHYD upregulated the expression of OCT4 (2.5-fold) and NANOG (fourfold) genes but not c-Myc or KLF4 in aHF and had no significant effect on the expression of all these genes in nbHF. VPA upregulated the expression of NANOG (twofold) in aHF and c-MYC in nbHF, while it downregulated the expression of NANOG in nbHF. The combination of HYD and VPA canceled the OCT4 and NANOG overexpression induced by HYD in aHF, while it reinforced the effects of VPA on c-Myc expression in nbHF. The HYD-induced overexpression of OCT4 and NANOG in aHDF was not dependent on demethylation of gene promoters, and no changes in the reprogramming efficiency were observed in both cell populations despite the downregulation of epigenetic genes DNMT1, ARID1A, and ARID2 in nbHF.ConclusionsOur data provide evidence that HYD regulates the expression of OCT4 and NANOG pluripotency genes as well as ARID1A and ARID2 genes, two members of the SWI/SNF chromatin remodeling complex family, in normal human dermal fibroblasts.

Coordination of hydralazine with Cu2+ at acidic pH promotes its oxidative degradation at neutral pH

Hydralazine (HL), a frequently prescribed oral antihypertensive drug, shows redox interactions with transition metals such as copper that are not fully understood. Copper may be present at high concentrations in the digestive tract and can affect oral drugs. An important parameter for such interactions is pH, which changes from acidic in the gastric juice to neutral pH in intestines. In this study, we examined interactions of HL with Cu2+ ions in conditions that mimic pH shift in the digestive tract using UV–Vis, Raman and EPR spectroscopy, cyclic voltammetry and oximetry. In the acidic solution, Cu2+ formed a stable mononuclear complex with two bidentate coordinated HL molecules. On the other hand, at neutral pH, Cu2+ initiated oxidation and degradation of HL. The degradation was more rapid in the HL-Cu2+ system that was initially prepared at acidic pH and then shifted to neutral pH. The formation of the complex at acidic pH increases the availability of Cu2+ for redox reactions after the shift to neutral pH at which Cu2+ is poorly soluble. These results imply that the change of pH along the digestive tract may promote HL degradation by allowing the formation of the complex at gastric pH which makes Cu2+ available for subsequent oxidation of HL at neutral pH.

Effect of the cholinergic system of the lateral periaqueductal gray (lPAG) on blood pressure and heart rate in normal and hydralazine hypotensive rats.

Due to the presence of the cholinergic system in the lateral periaqueductal gray (lPAG) column, the cardiovascular effects of acetylcholine (ACH) and its receptors in normotensive and hydralazine (HYD) hypotensive rats in this area were evaluated. After anesthesia, the femoral artery was cannulated and systolic blood pressure (SBP), mean arterial pressure (MAP), heart rate (HR), and also electrocardiogram for evaluation of low frequency (LF) and high frequency (HF) bands, important components of heart rate variability (HRV), were recorded. ACH, atropine (Atr, a muscarinic antagonist), and hexamethonium (Hex, an antagonist nicotinic) alone and together microinjected into lPAG, changes (Δ) of cardiovascular responses and normalized (n) LF, HF, and LF/HF ratio were analyzed. In normotensive rats, ACH decreased SBP and MAP, and enhanced HR while Atr and Hex did had no effects. In co-injection of Atr and Hex with ACH, only ACH+Atr significantly attenuated parameters. In HYD hypotension, ACH had no affect but Atr and Hex significantly improved the hypotensive effect. Co-injection of Atr and Hex with ACH decreased the hypotensive effect but the effect of Atr+ACH was higher. In normotensive rats, ACH decreased nLF, nHF, and nLF/nHF ratio. These parameters in the Atr +ACH group were significantly higher than in ACH group. In HYD hypotension nLF and nLF/nHF ratio increased which was attenuated by ACH. Also, Atr+ACH decreased nLF and nLF/nHF ratio and increased nHF. The cholinergic system of lPAG mainly via muscarinic receptors has an inhibitory effect on the cardiovascular system. Based on HRV assessment, peripheral cardiovascular effects are mostly mediated by the parasympathetic system.

PS-BPB07-5: HYPERTENSIVE STIMULI PROMOTE NEUROINFLAMMATION AND COGNITIVE IMPAIRMENT IN A PRESSURE-DEPENDENT MANNER

Objective: Hypertension greatly increases the risk for cognitive impairment, and is associated with inflammation of the brain. However, it is unclear to what extent there is neuroinflammation during hypertension and whether this promotes cognitive impairment. This study aimed to quantify neuroinflammatory and cognitive changes caused by administration of angiotensin II, and determine whether this is blood pressure-dependent. Design and method: Male C57Bl/6 mice were administered vehicle (saline; n = 33) or angiotensin II (0.7 mg/kg/d, n = 34) for 14 d via an osmotic minipump. A subset of mice also received hydralazine hydrochloride (50 mg/kg; n = 38) in their drinking water for 14 d after minipump implantation. Systolic blood pressure (SBP) was measured using tail-cuff; inflammation was assessed using flow cytometry and RNA sequencing; and recognition memory was evaluated using the novel object recognition test. Results: Angiotensin II infusion increased SBP and promoted accumulation of neutrophils, monocytes, T cells and B cells in the brain compared to vehicle infusion which was blunted by co-administration of hydralazine (n = 7–8, P < 0.05). Angiotensin II infusion also impaired recognition memory and this effect could be prevented by co-treatment with hydralazine (n = 11–12, P < 0.05). Angiotensin II infusion promoted differential expression of 1194 genes in whole brain hemisphere and 634 genes in hippocampus compared to vehicle infusion. Out of these genes, 295 in whole brain hemisphere and 125 in hippocampus were inflammation/immune-related (n = 6, P-adjusted < 0.05). Angiotensin II caused downregulation of genes involved in cognitive function and memory consolidation (Dusp1, Arc) and upregulation of genes involved in immune cell function, regulation and migration (H2-Ab1, H2-Q6, Il17rc, Fcrlb, Ltb, Ccl8, Itga9) in whole brain hemisphere (n = 6, P-adjusted < 0.05). In the hippocampus, a key region in learning and memory, angiotensin II promoted upregulation of genes involved in immune cell proliferation and differentiation (Il12rb2, Acvr1b, Sema3c) and apoptosis (Plxna3, Anxa11, Hyal1, Axin1) (n = 6, P-adjusted < 0.05). Co-treatment with hydralazine altered expression of all of these genes suggesting possible reversal of the transcriptomic changes induced by angiotensin II infusion (n = 6, P-adjusted < 0.05). Conclusion: Angiotensin II promotes neuroinflammation and cognitive impairment in a blood pressure-dependent manner. Co-treatment with hydralazine may reverse some of the transcriptomic changes induced by angiotensin II. Chronic neuroinflammation may be a contributing factor to cognitive impairment during hypertension and could be modulated by blood pressure reduction.

High glucose-induced increasing reactive nitrogen species accumulation triggered mitochondrial dysfunction, inflammation, and apoptosis in keratinocytes

Growing evidence indicates that skin injuries are a common complication of diabetes. However, the cellular and molecular mechanisms of high glucose (HG) environment trigger nitrosative stress-mediated inflammation and apoptosis in keratinocytes remains unknown. Here we investigated whether reactive nitrogen species (RNS) induced by HG environment restrain antioxidant activity, and mitochondrial dysfunction leading to inflammation, and apoptosis via stress signaling pathways in keratinocytes. Our results established that the HG environment enhanced the production of nitric oxide (NO) and peroxynitrite anion (ONOO−) by inducible NO synthase (iNOS) in keratinocytes. Overproduction of RNS in HG environment suppress the antioxidants activity leading to mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential (ΔΨm), increase in mitochondrial mass, decrease in mitochondrial transcription factor A(TFAM), increase in mitochondrial DNA (mtDNA) displacement loop (D-loop) and decrease in glycolytic flux concentration, which was attenuated by pharmacological inhibitors of NO/ONOO−, Nω-Nitro-l-argininemethyl ester hydrochloride (NAME)/hydralazine hydrochloride (Hyd.HCl). Excess production of RNS in HG environment restrained 8-oxoguanine DNA glycosylase-1 (OGG1) expression and increased 8-hydroxydeoxyguanosine (8-OHdG) accumulations in DNA were regulated by NO or ONOO−. Further, HG-induced RNA production caused an increase in the production of inflammatory mediators accompanied by activation of ERK1/2MAPK/Akt/tuberin-mTOR/IRF3 signaling cascade, lipid peroxidation (LPO), and protein carbonylation (PC) reactions followed by breakdown the cell-cell communication and apoptosis. Pre-treatment of cell with NAME/Hyd.HCl, diminished the expression of ERK1/2MAPK/Akt/tuberin-mTOR/IRF3, inflammatory mediators, and attenuated apoptosis in keratinocytes. Together, our results indicated that excess production of RNS in HG environment triggered inflammation and apoptosis, mediated by activation of ERK1/2MAPK/Akt/tuberin-mTOR/IRF3 signaling cascades in keratinocytes.

Development and Optimization of Gastro-Retentive Mucoadhesive Formulation of Hydralazine HCl

Development and Optimization of Gastro-Retentive Mucoadhesive Formulation of Hydralazine HCl