-
Journal of Cardiothoracic and Vascular... Jan 2024Vasodilatory hypotension is common in critically ill and perioperative patients, and is associated with adverse outcomes. As a nitric oxide production inhibitor,... (Meta-Analysis)
Meta-Analysis Review
Vasodilatory hypotension is common in critically ill and perioperative patients, and is associated with adverse outcomes. As a nitric oxide production inhibitor, methylene blue (MB) exerts its vasoconstrictor property and is an adjuvant for catecholamine-refractory vasodilatory shock. However, the effects of MB on clinically relevant outcomes remain unclear. Therefore, the authors performed a meta-analysis of randomized trials on MB in critically ill and perioperative patients. The authors searched through databases for randomized trials on MB in critically ill and perioperative patients, which yielded 11 studies consisting of 556 patients. The primary outcome was mortality at the longest follow-up. Secondary outcomes included hemodynamic parameters and organ dysfunction (PROSPERO: CRD42023409243). Nine out of the 11 included randomized trials reported mortality, which was significantly lower in the MB group (risk ratio, 0.60 [95% CI 0.43-0.84] p = 0.003), with findings confirmed in septic shock and cardiac surgery subgroups. The authors found reduced lengths of stay in the intensive care unit (mean difference [MD], -0.9 days [95% CI -1.06 to -0.77] p < 0.001) and in the hospital (MD, -2.2 days [95% CI, -2.68 to -1.70] p < 0.001) in the MB group. MB was associated with increased mean arterial pressure (MD, 8.4 mmHg [95% CI 5.01-11.75] p < 0.001) and systemic vascular resistance (MD, 94.5 dyn/s/cm [95% CI 17.73-171.15] p = 0.02), with no difference in cardiac output (standardized MD, 0.16 [95% CI, -0.25 to 0.57] p = 0.45). This meta-analysis showed that MB reverses vasodilation in critically ill and perioperative patients and might improve survival. Further adequately powered randomized trials are needed to confirm these findings.
Topics: Humans; Methylene Blue; Critical Illness; Randomized Controlled Trials as Topic; Shock; Shock, Septic; Hypotension
PubMed: 37880041
DOI: 10.1053/j.jvca.2023.09.037 -
Journal of Biochemical and Molecular... Mar 2024Phenothiazines (PTZs) are an emerging group of molecules showing effectiveness toward redox signaling and reduction of oxidative injury to cells, via the activation on... (Review)
Review
Phenothiazines (PTZs) are an emerging group of molecules showing effectiveness toward redox signaling and reduction of oxidative injury to cells, via the activation on Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Nrf2). Although several electrophilic and indirect Nrf2 activators have been reported, the risk of "off-target" effect due to the complexity of their molecular mechanisms of action, has aroused research interest toward non-electrophilic and direct modulators of Nrf2 pathway, such as PTZs. This review represents the first overview on the roles of PTZs as non-electrophilic Nrf2 activator and free radical scavengers, as well as on their potential therapeutic effects in oxidative stress-mediated diseases. Here, we provide a collective and comprehensive information on the PTZs ability to scavenge free radicals and activate the Nrf2 signaling pathway, with the aim to broaden the knowledge of their therapeutic potentials and to stimulate innovative research ideas.
Topics: Antioxidants; Free Radical Scavengers; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Phenothiazines
PubMed: 38369721
DOI: 10.1002/jbt.23661 -
Science Advances Oct 2023Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed...
Cancers in the central nervous system resist therapies effective in other cancers, possibly due to the unique biochemistry of the human brain microenvironment composed of cerebrospinal fluid (CSF). However, the impact of CSF on cancer cells and therapeutic efficacy is unknown. Here, we examined the effect of human CSF on glioblastoma (GBM) tumors from 25 patients. We found that CSF induces tumor cell plasticity and resistance to standard GBM treatments (temozolomide and irradiation). We identified nuclear protein 1 (NUPR1), a transcription factor hampering ferroptosis, as a mediator of therapeutic resistance in CSF. NUPR1 inhibition with a repurposed antipsychotic, trifluoperazine, enhanced the killing of GBM cells resistant to chemoradiation in CSF. The same chemo-effective doses of trifluoperazine were safe for human neurons and astrocytes derived from pluripotent stem cells. These findings reveal that chemoradiation efficacy decreases in human CSF and suggest that combining trifluoperazine with standard care may improve the survival of patients with GBM.
Topics: Humans; Glioblastoma; Trifluoperazine; Brain Neoplasms; Temozolomide; Chemoradiotherapy; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37878712
DOI: 10.1126/sciadv.adf1332 -
Experimental Neurology Nov 2023Neuroprotective effects have been the main focus of new treatment modalities for ischemic stroke. Phenothiazines, or chlorpromazine plus promethazine (C + P), are...
BACKGROUND
Neuroprotective effects have been the main focus of new treatment modalities for ischemic stroke. Phenothiazines, or chlorpromazine plus promethazine (C + P), are known to prevent the generation of free radicals and uptake of Ca by plasma membrane; they have a potential as a treatment for acute ischemic stroke (AIS). This study aims to investigate the role of endoplasmic reticulum (ER) stress-associated PERK-eIF2α pathway underlying the phenothiazine-induced neuroprotective effects after cerebral ischemia/reperfusion (I/R) injury.
METHODS
A total of 49 male Sprague Dawley rats (280-320 g) were randomly divided into 4 groups (n = 7 per group): (1) sham, (2) I/R that received 2 h of middle cerebral artery occlusion (MCAO), followed by 6 or 24 h of reperfusion, (3) MCAO treated by C + P without temperature control and (4) MCAO treated by C + P with temperature control. Human neuroblastoma (SH-SY5Y) cells were used in 5 groups: (1) control, (2) oxygen-glucose deprivation (OGD) for 2 h followed by reoxygenation (OGD/R), (3) OGD/R with C + P; (4) OGD/R with PERK inhibitor, GSK2656157, and (5) OGD/R with C + P and GSK2656157. The molecules of ER stress, unfolded protein response (UPR) (Bip, PERK, p-PERK, p-PERK/PERK, eIF2α, p-eIF2α, p-eIF2α/eIF2α), autophagy (ATG12, LC3II/I), and apoptosis (BAX, Bcl-XL) were measured at mRNA levels by real time PCR and protein levels by Western blotting.
RESULTS
In ischemic rats followed by reperfusion, expression of Bip, p-PERK/PERK, p-eIF2α/eIF2α, ATG12, and LC3II/I, as well as BAX were all significantly increased. These markers were significantly reduced by C + P at both 6 and 24 h of reperfusion. Anti-apoptotic Bcl-XL expression was increased, while pro-apoptotic BAX expression was decreased by C + P. In SH-SY5Y cell lines, both C + P and GSK2656157 significantly reduced the level of autophagy and apoptosis after I/R, respectively. The combination of GSK2656157 and C + P did not promote the same effect, suggesting that C + P did not induce any neuroprotective effect by inhibiting autophagy and apoptosis through the PERK-eIF2α pathway when this pathway was already blocked by GSK2656157. In general, the reduction in body temperature by phenothiazines was associated with better neuroprotection but it did not reach significant levels.
CONCLUSION
The combined treatment of C + P plays a crucial role in stroke therapy by inhibiting ER stress-mediated autophagy, thereby leading to reduced apoptosis and increased neuroprotection. Our findings highlight the PERK-eIF2α pathway as a central mechanism through which C + P exerts its beneficial effects. The results from this study may pave the way for the development of more targeted and effective treatments for stroke patients.
Topics: Animals; Humans; Male; Rats; Apoptosis; Autophagy; bcl-2-Associated X Protein; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Infarction, Middle Cerebral Artery; Ischemic Stroke; Neuroblastoma; Neuroprotective Agents; Phenothiazines; Rats, Sprague-Dawley; Reperfusion Injury
PubMed: 37673390
DOI: 10.1016/j.expneurol.2023.114524 -
Journal of Basic and Clinical... Jan 2024Alzheimer's disease (AD) is spreading its root disproportionately among the worldwide population. Many genes have been identified as the hallmarks of AD. Based upon the... (Review)
Review
Alzheimer's disease (AD) is spreading its root disproportionately among the worldwide population. Many genes have been identified as the hallmarks of AD. Based upon the knowledge, many clinical trials have been designed and conducted. Attempts have been made to alleviate the pathology associated with AD by targeting the molecular products of these genes. Irrespective of the understanding on the genetic component of AD, many clinical trials have failed and imposed greater challenges on the path of drug discovery. Therefore, this review aims to identify research and review articles to pinpoint the limitations of drug candidates (thiethylperazine, CT1812, crenezumab, CNP520, and lecanemab), which are under or withdrawn from clinical trials. Thorough analysis of the cross-talk pathways led to the identification of many confounding factors, which could interfere with the success of clinical trials with drug candidates such as thiethylperazine, CT1812, crenezumab, and CNP520. Though these drug candidates were enrolled in clinical trials, yet literature review shows many limitations. These limitations raise many questions on the rationale behind the enrollments of these drug candidates in clinical trials. A meticulous prior assessment of the outcome of clinical studies may stop risky clinical trials at their inceptions. This may save time, money, and resources.
Topics: Humans; Alzheimer Disease; Thiethylperazine
PubMed: 38491747
DOI: 10.1515/jbcpp-2023-0264 -
Nature Communications Sep 2023Preventing tau aggregation is a potential therapeutic strategy in Alzheimer's disease and other tauopathies. Recently, liquid-liquid phase separation has been found to...
Preventing tau aggregation is a potential therapeutic strategy in Alzheimer's disease and other tauopathies. Recently, liquid-liquid phase separation has been found to facilitate the formation of pathogenic tau conformations and fibrillar aggregates, although many aspects of the conformational transitions of tau during the phase transition process remain unknown. Here, we demonstrate that the tau aggregation inhibitor methylene blue promotes tau liquid-liquid phase separation and accelerates the liquid-to-gel transition of tau droplets independent of the redox activity of methylene blue. We further show that methylene blue inhibits the conversion of tau droplets into fibrils and reduces the cytotoxicity of tau aggregates. Although gelation slows down the mobility of tau and tubulin, it does not impair microtubule assembly within tau droplets. These findings suggest that methylene blue inhibits tau amyloid fibrillization and accelerates tau droplet gelation via distinct mechanisms, thus providing insights into the activity of tau aggregation inhibitors in the context of phase transition.
Topics: Humans; Methylene Blue; Alzheimer Disease; Amyloidogenic Proteins; Cytoskeleton; Phase Transition
PubMed: 37673952
DOI: 10.1038/s41467-023-41241-6 -
Acta Psychiatrica Scandinavica Apr 2024Although not approved for the treatment of anxiety disorders (except trifluoperazine) there is ongoing off-label, unapproved use of first-generation antipsychotics... (Review)
Review
BACKGROUND
Although not approved for the treatment of anxiety disorders (except trifluoperazine) there is ongoing off-label, unapproved use of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) for anxiety disorders. There have been systematic reviews and meta-analyses on the use of antipsychotics in anxiety disorders, most of which focused on SGAs.
OBJECTIVE
The specific aims of this umbrella review are to: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to traditional antidepressant treatments and other nonantipsychotic medications; (2) Compare monotherapy with antipsychotics to first-line treatments for anxiety disorders in terms of effectiveness, risks, and side effects. The review protocol is registered on PROSPERO (CRD42021237436).
METHODS
An initial search was undertaken to identify systematic reviews and meta-analyses from inception until 2020, with an updated search completed August 2021 and January 2023. The searches were conducted in PubMed, MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), CINAHL Complete (EBSCOhost), and the Cochrane Library through hand searches of references of included articles. Review quality was measured using the AMSTAR-2 (A MeaSurement Tool to Assess Systematic Reviews) scale.
RESULTS
The original and updated searches yielded 1796 and 3744 articles respectively, of which 45 were eligible. After final review, 25 systematic reviews and meta-analyses were included in the analysis. Most of the systematic reviews and meta-analyses were deemed low-quality through AMSTAR-2 with only one review being deemed high-quality. In evaluating the monotherapies with antipsychotics compared with first-line treatments for anxiety disorder there was insufficient evidence due to flawed study designs (such as problems with randomization) and small sample sizes within studies. There was limited evidence suggesting efficacy of antipsychotic agents in anxiety disorders other than quetiapine in generalized anxiety disorder (GAD).
CONCLUSIONS
This umbrella review indicates a lack of high-quality studies of antipsychotics in anxiety disorders outside of the use of quetiapine in GAD. Although potentially effective for anxiety disorders, FGAs and SGAs may have risks and side effects that outweigh their efficacy, although there were limited data. Further long-term and larger-scale studies of antipsychotics in anxiety disorders are needed.
Topics: Humans; Antipsychotic Agents; Anxiety Disorders; PubMed; Quetiapine Fumarate; Trifluoperazine; Systematic Reviews as Topic; Meta-Analysis as Topic
PubMed: 38382649
DOI: 10.1111/acps.13669 -
Hand (New York, N.Y.) Oct 2023Failure to recognize a potential wrist arthrotomy may lead to missed septic arthritis and devastating sequelae. The saline load test is routinely used to recognize...
BACKGROUND
Failure to recognize a potential wrist arthrotomy may lead to missed septic arthritis and devastating sequelae. The saline load test is routinely used to recognize traumatic arthrotomies of other joints; however, there are limited data optimizing this test for the wrist. The purpose of this study was to investigate and perform saline load testing to identify traumatic arthrotomies of the wrist.
METHODS
This was a cadaveric study of 15 wrists. Traumatic arthrotomies were created using a blunt trocar through the 3-4 portal. A 3-mL syringe with 0.1 mL markings was used to inject methylene blue dyed saline into the wrist through the 1-2 portal. Once extravasation was visible from the atherectomized site, the volume was recorded.
RESULTS
The mean (range) volume injected to identify the arthrotomy of all wrists was 1.22 mL (range, 0.1-3.1 mL). Multivariate regression demonstrated that cadaver age, laterality, and extension range of motion were not significantly associated with the injected saline volume at extravasation ( > .05, each). Greater joint range of motion was independently associated with higher saline volume load for extravasation (odds ratio: 1.049; 95% confidence interval: 1.024-1.075; = .003).
CONCLUSIONS
We found that 2.68 and 3.02 mL of methylene blue dyed saline offered 95% and 99% sensitivity, respectively, for diagnosing traumatic wrist arthrotomy. The maximum volume of saline needed to recognize an arthrotomy was 3.1 mL. We recommend this be the minimum volume used to evaluate a traumatic wrist arthrotomy.
Topics: Humans; Wrist; Methylene Blue; Injections, Intra-Articular; Arthroscopy; Wrist Joint; Coloring Agents
PubMed: 35343259
DOI: 10.1177/15589447211043194 -
Pharmaceutical Biology Dec 2023Diabetic wounds (DW) are a complication of diabetes and slow wound healing is the main manifestation. Methylene blue (MB) has been shown to exhibit therapeutic effects...
CONTEXT
Diabetic wounds (DW) are a complication of diabetes and slow wound healing is the main manifestation. Methylene blue (MB) has been shown to exhibit therapeutic effects on diabetes-related diseases.
OBJECTIVE
To investigate the mechanisms of action of MB-nanoemulsion (NE) in the treatment of DW.
MATERIALS AND METHODS
The concentration of MB-NE used in the and experiments was 0.1 mg/mL. Streptozocin-induced diabetic mice were used as models. The mice were separated into nondiabetic, diabetic, MB-NE treated, and NE-treated groups. Intervention of high glucose-induced human umbilical vein endothelial cells using MB-NE. The mechanism by which MB-NE promotes DW healing is investigated by combining histological analysis, immunofluorescence analysis, TUNEL and ROS assays and western blotting.
RESULTS
In diabetic mice, the MB-NE accelerated DW healing ( < 0.05), promoted the expression of endothelial cell markers (α-SMA, CD31 and VEGF) ( < 0.05), and reduced TUNEL levels. , MB accelerated the migration rate of cells ( < 0.05); promoted the expression of CD31, VEGF, anti-apoptotic protein Bcl2 ( < 0.05) and decreased the expression of the pro-apoptotic proteins cleaved caspase-3 and Bax ( < 0.05). MB upregulated the expression of Nrf2, catalase, HO-1 and SOD2 ( < 0.05). In addition, MB reduced the immunofluorescence intensity of TUNEL and ROS in cells and reduced apoptosis. The therapeutic effect of MB was attenuated after treatment with an Nrf2 inhibitor (ML385).
DISCUSSION AND CONCLUSION
This study provides a foundation for the application of MB-NE in the treatment of DW.
Topics: Humans; Animals; Mice; Diabetes Mellitus, Experimental; Methylene Blue; NF-E2-Related Factor 2; Reactive Oxygen Species; Vascular Endothelial Growth Factor A; Human Umbilical Vein Endothelial Cells
PubMed: 37691404
DOI: 10.1080/13880209.2023.2254341