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Life Sciences Jul 2022The current study aimed to elucidate the neurotoxic potential of DOX to induce AD-like pathology paying attention to the role of wingless-integrated/β-catenin...
AIMS
The current study aimed to elucidate the neurotoxic potential of DOX to induce AD-like pathology paying attention to the role of wingless-integrated/β-catenin (Wnt/β-catenin) signaling pathway. A major aim was to evaluate the efficacy of infliximab (IFX) either individually or in combination with 2-mercaptoethane sulfonate sodium (MESNA) on the DOX-induced neurotoxicity in rats.
METHODOLOGY
AD-like pathology was induced in adult male Wistar rats by intraperitoneal (i.p.) administration of DOX at a dose of 3.5 mg/kg twice a week for 3 weeks. DOX-injected rats were then treated with either INF at a single dose of 5 mg/kg i.p. (IFX group), MESNA at a dose of 160 mg/kg/day i.p. for 4 weeks (MESNA group) or their combination at the same specified doses (INF + MESNA group). At the end of the study period, behavioral assessment was performed and the brain tissue samples were harvested at sacrifice.
KEY FINDINGS
DOX-treated rats significantly exhibited AD-like brain injury, increased amyloid burden, enhanced neuroinflammation and apoptosis, and multifocal histological injury in the cerebral cortex with widespread vacuolations. IFX and MESNA significantly reversed all the aforementioned detrimental effects in the DOX-treated rats.
SIGNIFICANCE
The study has provided sufficient evidence of the potential of IFX and/or MESNA to ameliorate the DOX-induced neurotoxicity, with the best improvement observed with their combined administration. A new insight has been introduced into the critical role of Wnt/β-catenin activation.
Topics: Alzheimer Disease; Animals; Doxorubicin; Infliximab; Male; Mesna; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Wnt Signaling Pathway; beta Catenin
PubMed: 35523286
DOI: 10.1016/j.lfs.2022.120613 -
Biochemistry May 2022Microbial anaerobic oxidation of alkanes intrigues the scientific community by way of its impact on the global carbon cycle, and its biotechnological applications.... (Review)
Review
Microbial anaerobic oxidation of alkanes intrigues the scientific community by way of its impact on the global carbon cycle, and its biotechnological applications. Archaea are proposed to degrade short- and long-chain alkanes to CO by reversing methanogenesis, a theoretically reversible process. The pathway would start with alkane activation, an endergonic step catalyzed by methyl-coenzyme M reductase (MCR) homologues that would generate alkyl-thiols carried by coenzyme M. While the methane-generating MCR found in methanogens has been well characterized, the enzymatic activity of the putative alkane-fixing counterparts has not been validated so far. Such an absence of biochemical investigations contrasts with the current explosion of metagenomics data, which draws new potential alkane-oxidizing pathways in various archaeal phyla. Therefore, validating the physiological function of these putative alkane-fixing machines and investigating how their structures, catalytic mechanisms, and cofactors vary depending on the targeted alkane have become urgent needs. The first structural insights into the methane- and ethane-capturing MCRs highlighted unsuspected differences and proposed some explanations for their substrate specificity. This Perspective reviews the current physiological, biochemical, and structural knowledge of alkyl-CoM reductases and offers fresh ideas about the expected mechanistic and chemical differences among members of this broad family. We conclude with the challenges of the investigation of these particular enzymes, which might one day generate biofuels for our modern society.
Topics: Alkanes; Anaerobiosis; Archaea; Catalysis; Mesna; Methane; Oxidation-Reduction; Oxidoreductases; Phylogeny
PubMed: 35500274
DOI: 10.1021/acs.biochem.2c00135 -
The Journal of Pharmacology and... Jan 2024Inhalation of high levels of sulfur mustard (SM), a potent vesicating and alkylating agent used in chemical warfare, results in acutely lethal pulmonary damage. Sodium...
Inhalation of high levels of sulfur mustard (SM), a potent vesicating and alkylating agent used in chemical warfare, results in acutely lethal pulmonary damage. Sodium 2-mercaptoethane sulfonate (mesna) is an organosulfur compound that is currently Food and Drug Administration (FDA)-approved for decreasing the toxicity of mustard-derived chemotherapeutic alkylating agents like ifosfamide and cyclophosphamide. The nucleophilic thiol of mesna is a suitable reactant for the neutralization of the electrophilic group of toxic mustard intermediates. In a rat model of SM inhalation, treatment with mesna (three doses: 300 mg/kg intraperitoneally 20 minutes, 4 hours, and 8 hours postexposure) afforded 74% survival at 48 hours, compared with 0% survival at less than 17 hours in the untreated and vehicle-treated control groups. Protection from cardiopulmonary failure by mesna was demonstrated by improved peripheral oxygen saturation and increased heart rate through 48 hours. Additionally, mesna normalized arterial pH and pACO Airway fibrin cast formation was decreased by more than 66% in the mesna-treated group at 9 hour after exposure compared with the vehicle group. Finally, analysis of mixtures of a mustard agent and mesna by a 5,5'-dithiobis(2-nitrobenzoic acid) assay and high performance liquid chromatography tandem mass spectrometry demonstrate a direct reaction between the compounds. This study provides evidence that mesna is an efficacious, inexpensive, FDA-approved candidate antidote for SM exposure. SIGNIFICANCE STATEMENT: Despite the use of sulfur mustard (SM) as a chemical weapon for over 100 years, an ideal drug candidate for treatment after real-world exposure situations has not yet been identified. Utilizing a uniformly lethal animal model, the results of the present study demonstrate that sodium 2-mercaptoethane sulfonate is a promising candidate for repurposing as an antidote, decreasing airway obstruction and improving pulmonary gas exchange, tissue oxygen delivery, and survival following high level SM inhalation exposure, and warrants further consideration.
Topics: Rats; Animals; Mustard Gas; Mesna; Antidotes; Lung; Sodium; Chemical Warfare Agents
PubMed: 37541763
DOI: 10.1124/jpet.123.001683 -
Neurotoxicity Research Jun 2021Peripheral neuropathy and cognitive impairments following cisplatin administration may interfere with the clinical usage of the drug. Mesna is a chemoprotective agent...
Peripheral neuropathy and cognitive impairments following cisplatin administration may interfere with the clinical usage of the drug. Mesna is a chemoprotective agent with anti-inflammatory and anti-oxidant effects. Our study aimed to investigate the protective effects of mesna against cisplatin-induced neurotoxicity. Neurotoxicity was induced by the administration of 2.5 mg/kg cisplatin twice a week for four consecutive weeks in male Wistar rats. The neuroprotective effect of mesna (150 mg/kg/day) was evaluated through behavioral, electrophysiological, and molecular studies. Cisplatin treatment caused passive avoidance memory impairment, increased anxiety-like behaviors, altered thermal sensitivity, and decreased muscle strength in a grip strength test. Our electrophysiological studies indicated that administration of cisplatin induced peripheral sensory neuropathy and decreased the amplitudes of the compound action potential of sensory nerves. Cisplatin administration increased MDA and 4-HNE levels and decreased anti-oxidant (SOD and GPx) enzymes. Proinflammatory cytokines (IL-1β and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were increased by cisplatin treatment. Morphological alterations were observed in the dorsal root ganglion (DRG) of cisplatin-treated rats. Cognitive impairments, anxiety, muscle strength, and thermal sensitivity changes induced by cisplatin were improved with mesna treatment. The reduced conduction velocity in sensory nerves was recovered in the cisplatin + mesna group. Mesna partially alleviated redox imbalance, reduced the proinflammatory cytokines, and MMP-2/9 levels. Mesna administration also relieved the morphological changes in DRG of cisplatin-treated rats. In conclusion, our results revealed that mesna can alleviate cisplatin-induced central and peripheral nervous system toxicity. These results support the concept that chemotherapy-induced neuropathy can be partially inhibited via mesna.
Topics: Animals; Antineoplastic Agents; Cisplatin; Electrophysiological Phenomena; Inflammation Mediators; Male; Memory Disorders; Mesna; Neuroprotective Agents; Oxidative Stress; Protective Agents; Rats; Rats, Wistar
PubMed: 33216283
DOI: 10.1007/s12640-020-00315-9 -
Annals of Medicine and Surgery (2012) Nov 2022Spine surgery and spinal fusion surgery are rising. Revision rates following initial surgery are between 8 and 45%. Epidural fibrosis is a common response to spine...
UNLABELLED
Spine surgery and spinal fusion surgery are rising. Revision rates following initial surgery are between 8 and 45%. Epidural fibrosis is a common response to spine surgery for most patients and increases complications in revision surgery. Previous research suggests using MESNA (Sodium 2-mercaptoethane sulfonate) in combination with mechanical blunt dissection safely reduces surgical complications. MESNA is a mucolytic agent which selectively cleaves disulphide bonds involved in the adherence and strength of fibrosis, meaning cutting instruments are not needed. The Chemically Assisted DISSection (CADISS®) System is an optimised non-cutting surgical device, consisting of a reconstitution cartridge for MESNA preparation, irrigated surgical instruments, and a footswitch to control MESNA release. This is the first study to investigate the use of the CADISS® System in revision spine surgery.
METHODS
This was a prospective, open label, observational case study. We enrolled 21 patients for revision spine surgery with the CADISS® System at two Belgium sites. The primary assessment was the number of successful removals of epidural fibrosis without cutting. The amount of MESNA used, total dissection and procedure time were recorded. For secondary criterion, the surgeons assessed global satisfaction, facilitation of dissection, quickness of action, usability, bleeding reduction and visualisation of the cleavage plane using an 11-point Likert scale (0-10). Due to the exploratory nature, no formal statistical analysis was planned. We calculated the percentage and confidence interval of successful procedures, the medians and corresponding interquartile range of the Likert criterion, and the mean (±SD) of the amount of MESNA used, CADISS® dissection time and total procedure time.
RESULTS
24 fibrosis dissections were performed in 19 patients and 23 were successful (95.8%, CI: 78.9%; 99.9%). The mean amount of MESNA used, mean dissection time and procedure time were 16 ml (±4.94), 16.5 min (±16.1) and 86.3 min (±25.1), respectively. No dural tears were reported. The mean global satisfaction score was 9.0 (8.0-9.0). All other Likert criterion had scores of 8.0 or 9.0, excluding quickness of action, which scored 7.0 (6.0-9.0).
CONCLUSIONS
The CADISS® System in revision spine surgery has potential to effectively reduce dissection complications.
PubMed: 36389182
DOI: 10.1016/j.amsu.2022.104718 -
Journal of Pediatric Hematology/oncology Nov 2022Ifosfamide is an antitumor agent with activity against various malignancies in pediatric patients. As a prodrug, ifosfamide requires metabolic activation, which occurs...
Ifosfamide is an antitumor agent with activity against various malignancies in pediatric patients. As a prodrug, ifosfamide requires metabolic activation, which occurs via a saturable, multistep equilibrium-based process. Due to these metabolic characteristics, the method of administration can affect its therapeutic and toxic effects. This single-center, retrospective review describes the tolerability of continuous infusion and bolus administration of ifosfamide in 10 pediatric patients with Ewing sarcoma. The primary objective was to report the hematologic toxicities of patients with differing administration methods. Secondary objectives included collecting information on nonhematologic toxicities and incidence of treatment delays and dose reductions. Ultimately, 48 cycles of ifosfamide were administered as bolus administration and 24 as continuous infusion. Patients receiving bolus administration had lower hemoglobin and platelet nadirs resulting in more transfusions and treatment delays when compared proportionally to continuous infusion. With the results of this case series, continuous infusion ifosfamide appears to be safe and feasible for outpatient administration and may offer an advantage from a hematologic adverse event profile but would need to be confirmed in a larger cohort.
Topics: Humans; Child; Ifosfamide; Mesna; Infusions, Intravenous; Neoplasms; Drug Administration Schedule
PubMed: 34862353
DOI: 10.1097/MPH.0000000000002361 -
Journal of Inorganic Biochemistry Feb 2020Here, we show that mesna (sodium-2-mercaptoethane sulfonate), primarily used to prevent nephrotoxicity and urinary tract toxicity caused by chemotherapeutic agents such...
Here, we show that mesna (sodium-2-mercaptoethane sulfonate), primarily used to prevent nephrotoxicity and urinary tract toxicity caused by chemotherapeutic agents such as cyclophosphamide and ifosfamide, modulates the catalytic activity of lactoperoxidase (LPO) by binding tightly to the enzyme, functioning either as a one electron substrate for LPO Compounds I and II, destabilizing Compound III. Lactoperoxidase is a hemoprotein that utilizes hydrogen peroxide (HO) and thiocyanate (SCN) to produce hypothiocyanous acid (HOSCN), an antimicrobial agent also thought to be associated with carcinogenesis. Our results revealed that mesna binds stably to LPO within the SCN binding site, dependent of the heme iron moiety, and its combination with LPO-Fe(III) is associated with a disturbance in the water molecule network in the heme cavity. At low concentrations, mesna accelerated the formation and decay of LPO compound II via its ability to serve as a one electron substrate for LPO compounds I and II. At higher concentrations, mesna also accelerated the formation of Compound II but it decays to LPO-Fe(III) directly or through the formation of an intermediate, Compound I*, that displays characteristic spectrum similar to that of LPO Compound I. Mesna inhibits LPO's halogenation activity (IC value of 9.08 μM) by switching the reaction from a 2e to a 1e pathway, allowing the enzyme to function with significant peroxidase activity (conversion of HO to HO without generation of HOSCN). Collectively, mesna interaction with LPO may serve as a potential mechanism for modulating its steady-state catalysis, impacting the regulation of local inflammatory and infectious events.
Topics: Enzyme Inhibitors; Kinetics; Lactoperoxidase; Mesna; Protective Agents
PubMed: 31734539
DOI: 10.1016/j.jinorgbio.2019.110911 -
Otolaryngologia Polska = the Polish... Jul 2023<b>Introduction:</b> Surgery is still the method of choice in chronic otitis media with cholesteatoma. Except for some specific clinical situations, classic...
<b>Introduction:</b> Surgery is still the method of choice in chronic otitis media with cholesteatoma. Except for some specific clinical situations, classic canal wall up technique (CWU), remains a gold standard as a primary treatment in most departments. Unfortunately, the risk of recurrence in such an approach is estimated at 9 to even 70%. This fact prompts researchers to look for ways to reduce those unfavourable statistics. One of the recognized methods supporting the removal of cholesteatoma is the intraoperative use of mesna (sodium 2-mercaptoethanesulfonate). This synthetic sulphur compound disrupts disulfide bridges in polypeptide chains, thanks to which it facilitates matrix preparation.</br></br> <b>Aim:</b> To evaluate the effect of intraoperative use of mesna on the treatment outcomes in patients with chronic otitis media with cholesteatoma operated on by means of the canal wall up technique (CWU).</br></br> <b>Material and methods:</b> 459 surgical reports of patients with middle ear cholesteatoma were analyzed. In total, 52 adult patients with no history of previous ear surgery operated on by means of the CWU technique by the same experienced otosurgeon with all follow-up data available were included in the study. Twenty-six were operated on with the use of mesna (mesna group) and 26 by means of the classic CWU technique (control / no-mesna group). There were 28 women and 24 men with a mean age of 41 years.</br></br> <b>Main Outcome Measure(s):</b> Postoperative hearing results and cholesteatoma recidivism rate.</br></br> <b>Results:</b> Overall recidivism rate was 21.15 %. It was higher in the no-mesna (26.9%) than in the mesna group (15.4%) - although the outcomes were better in the mesna group, the difference was not statistically significant (P = 0.49715). Hearing gain was better in the mesna than in the no-mesna group (10 dB vs 7 dB), but the difference was not statistically significant (P = 0.20089).</br></br> <b>Conclusions:</b> Our preliminary results show that mesna reduces recidivism rates in patients with cholesteatoma. Further study with the analysis of a larger group of patients is needed to prove it statistically.
PubMed: 37772375
DOI: 10.5604/01.3001.0016.3415 -
Journal of Voice : Official Journal of... Jan 2024Mesna triggers chemical dissection in tissues by breaking down disulfide bonds and is used during surgical dissections in several areas. In this study, we aimed to...
OBJECTIVE
Mesna triggers chemical dissection in tissues by breaking down disulfide bonds and is used during surgical dissections in several areas. In this study, we aimed to investigate the effect of submucosal mesna infiltration on microflap elevation and the histopathological findings of its effects on the vocal fold lamina propria in a rabbit model.
METHODS
Eight adult male New Zealand white rabbits were used in the study. Each vocal fold was randomized, and 0.1 mL of mesna was injected into one-fold and 0.1 mL of saline to the contralateral fold. An incision was made on the epithelium and elevation was performed. The animals were sacrificed after two weeks, and the vocal folds were excised. Inflammatory response, fibrosis, and epithelial thickness were evaluated with hematoxylin eosin and Masson's Trichrome staining. Elevation time and histopathological features were compared between the two groups.
RESULTS
The elevation time (20.9 ± 1.6 second) in the saline group was significantly higher (P < 0.05) than in the mesna group (15.0 ± 3.4 second). The inflammation (1.3 ± 0.5 vs. 1.1 ± 1.0, respectively) and fibrosis scores (1.0 ± 0.8 vs. 0.8 ± 0.7, respectively) did not differ significantly (P > 0.05 in both). Epithelial thickness (12.5 ± 4.7 vs. 10.3 ± 5.3, respectively) did not differ significantly (P ˃ 0.05) in the mesna and saline groups either.
CONCLUSION
We determined that mesna facilitates the microflap elevation of the vocal folds in rabbits and does not damage the histological structure of vocal folds. This study encourages future studies to evaluate the use of mesna, now actively used across disciplines, in phonosurgery as well.
Topics: Rabbits; Male; Animals; Vocal Cords; Mesna; Mucous Membrane; Injections; Fibrosis
PubMed: 34404583
DOI: 10.1016/j.jvoice.2021.07.011 -
Cureus Feb 2024Polyarteritis nodosa (PAN) is a connective tissue disease that affects arteries, causing necrotizing inflammation that can weaken the arterial walls, dilatation into...
Polyarteritis nodosa (PAN) is a connective tissue disease that affects arteries, causing necrotizing inflammation that can weaken the arterial walls, dilatation into aneurysms, and rupture in some cases. We present a case of a male with acute abdomen from aneurysmal rupture. The 48-year-old patient with a history of polysubstance use including cocaine and methamphetamines was admitted for acute hypoxic respiratory failure secondary to coronavirus disease 2019 (COVID-19) pneumonia and treated with broad-spectrum antibiotics and steroids. He also reported generalized abdominal pain and discomfort, and examination revealed abdominal distension that was diffusely tender on palpation, bowel sounds intact. Laboratory workup showed a progressive drop in hemoglobin requiring blood transfusions, no coagulopathy, anion gap metabolic acidosis, and lactic acidosis. Abdominal CT showed a 2 cm lobulated saccular aneurysm involving either the left gastric artery or splenic artery, associated with an extensive moderate amount of hemoperitoneum with hematomas (largest measuring up to 8.6 cm) abutting the gastric fundus and greater curvature of the stomach, which was likely secondary to aneurysmal rupture. Additionally, several other mesenteric vessels displayed some degree of dilation. Interventional radiology (IR)-guided splenic artery embolization for splenic artery aneurysm was done, after which his hemoglobin remained stable. The patient was given vaccine recommendations since splenic artery embolization would lead to asplenia. The aneurysms were attributed to either cocaine-related aneurysms or polyarteritis nodosa with visceral artery aneurysms. He denied rashes, oral ulcers, joint pain, subcutaneous nodules, blood in the urine, history of hepatitis or syphilis. Tertiary syphilis was ruled out after the Venereal Disease Research Laboratory (VDRL) test and rapid plasma reagin (RPR) test were negative. Complement C3 and C4 levels were normal. He was treated with high-dose IV methylprednisone after infection was ruled out. Due to the severity of PAN, therapy with IV cyclophosphamide therapy 15 mg/kg once every two weeks for three doses was initiated, followed by 15 mg/kg once every three weeks for three to six months (in combination with glucocorticoids prednisone 1 mg/kg body weight with slow taper). Cyclophosphamide was given with IV hydration and mesna. The presentation of PAN can vary widely. Most commonly, individuals experience symptoms such as fatigue, weight loss, fever, and chills. However, in rare cases, patients may present with isolated abdominal pain, similar to our patient. It's crucial to note that the rupture of an aneurysm can manifest as an acute abdominal issue, potentially leading to life-threatening situations. Immediate interventions to control bleeding are imperative in such cases. The treatment of PAN has a high success rate when a combination of cyclophosphamide and steroids is administered.
PubMed: 38558645
DOI: 10.7759/cureus.55143