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BioFactors (Oxford, England) Jun 2024Neuropathy occurs due to damage to the peripheral/central nervous system either due to injury, disease, or drug usage. Increased endoplasmic reticulum (ER) stress is...
Neuropathy occurs due to damage to the peripheral/central nervous system either due to injury, disease, or drug usage. Increased endoplasmic reticulum (ER) stress is observed in neuropathy. ER stress also leads to a block in autophagy amplifying neuropathic pain. 6-Bromoindirubin-3'-oxime (6-BIO) is an inhibitor of GSK-3β which suppresses mTOR activity thereby increasing autophagy. Tunicamycin (TM)-mediated ER stress and diabetic rat models were used to elucidate the role of ER stress and autophagy in mitigation of neuropathic pain by 6-BIO. Pain was assessed by behavioral studies in ER stressed/diabetic rats having neuropathy. Western blotting, RT-PCR, and fluorescence microscopy were used to assess the level of autophagy and ER stress after TM and 6-BIO treatment in SH-SY5Y neurons. Intraplantar injection of TM in rats led to peripheral neuropathy which was reduced upon 6-BIO injection. 6-BIO also reduced pain in animals exhibiting diabetic peripheral neuropathy. Modulation in the markers of autophagy (p-mTOR, LC-3, and SQSTM1/p62) shows that 6-BIO induces autophagolysosome formation post TM treatment. Concomitantly, 6-BIO reduces ER stress and c-Fos expression-a neuronal activity and pain marker. Alleviation of pain by the inhibition of ER stress and increased formation of autolysosomes by 6-BIO can be harnessed for treating peripheral neuropathy.
PubMed: 38866585
DOI: 10.1002/biof.2088 -
Chemical Communications (Cambridge,... Jun 2024The total synthesis of 1,4a-di--pancratistatin, a novel stereoisomer of the anti-tumor alkaloid pancratistatin, was achieved in 14 steps starting from D-mannitol. The...
The total synthesis of 1,4a-di--pancratistatin, a novel stereoisomer of the anti-tumor alkaloid pancratistatin, was achieved in 14 steps starting from D-mannitol. The construction of the pancratistatin skeleton involved conjugate addition of organocuprate to a nitrosoolefin, which was generated from inosose oxime. This was followed by stereoselective reduction of the oxime to an amine and site-selective formylation. Biological evaluations revealed that the newly synthesized compounds exhibit cytotoxicity toward cancer cells and significant ferroptosis inhibitory activity. These compounds constitute a promising small-molecule library for the development of potent bioactive agents.
Topics: Amaryllidaceae Alkaloids; Humans; Stereoisomerism; Cell Line, Tumor; Isoquinolines; Antineoplastic Agents; Drug Screening Assays, Antitumor; Molecular Structure; Cell Proliferation; Structure-Activity Relationship; Cell Survival
PubMed: 38864269
DOI: 10.1039/d4cc02199a -
Scientific Reports Jun 2024There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce... (Meta-Analysis)
Meta-Analysis
A systematic review and meta-analysis, investigating dose and time of fluvoxamine treatment efficacy for COVID-19 clinical deterioration, death, and Long-COVID complications.
There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce the severity of the disease and prevent the need for hospitalization to avoid stress on healthcare systems worldwide. The repurposing of drugs to prevent clinical deterioration of COVID-19 patients was trialed in many studies using many different drugs. Fluvoxamine (an SSRI and sigma-1 receptor agonist) was initially identified to potentially provide beneficial effects in COVID-19-infected patients, preventing clinical deterioration and the need for hospitalization. Fourteen clinical studies have been carried out to date, with seven of those being randomized placebo-controlled studies. This systematic review and meta-analysis covers the literature from the outbreak of SARS-CoV-2 in late 2019 until January 2024. Search terms related to fluvoxamine, such as its trade names and chemical names, along with words related to COVID-19, such as SARS-CoV-2 and coronavirus, were used in literature databases including PubMed, Google Scholar, Scopus, and the ClinicalTrials.gov database from NIH, to identify the trials used in the subsequent analysis. Clinical deterioration and death data were extracted from these studies where available and used in the meta-analysis. A total of 7153 patients were studied across 14 studies (both open-label and double-blind placebo-controlled). 681 out of 3553 (19.17%) in the standard care group and 255 out of 3600 (7.08%) in the fluvoxamine-treated group experienced clinical deterioration. The estimated average log odds ratio was 1.087 (95% CI 0.200 to 1.973), which differed significantly from zero (z = 2.402, p = 0.016). The seven placebo-controlled studies resulted in a log odds ratio of 0.359 (95% CI 0.1111 to 0.5294), which differed significantly from zero (z = 3.103, p = 0.002). The results of this study identified fluvoxamine as effective in preventing clinical deterioration, and subgrouping analysis suggests that earlier treatment with a dose of 200 mg or above provides the best outcomes. We hope the outcomes of this study can help design future studies into respiratory viral infections and potentially improve clinical outcomes.
Topics: Fluvoxamine; Humans; COVID-19 Drug Treatment; COVID-19; SARS-CoV-2; Treatment Outcome; Clinical Deterioration; Selective Serotonin Reuptake Inhibitors
PubMed: 38862591
DOI: 10.1038/s41598-024-64260-9 -
Human & Experimental Toxicology 2024Organophosphorus (OP) poisoning is a significant cause of morbidity and mortality worldwide. Recent research has explored new approaches to improving treatment options,... (Randomized Controlled Trial)
Randomized Controlled Trial
Organophosphorus (OP) poisoning is a significant cause of morbidity and mortality worldwide. Recent research has explored new approaches to improving treatment options, which present several challenges. This study aimed to evaluate the role of fresh frozen plasma (FFP) as an adjunctive therapy for acute OP intoxication. A prospective single-blinded randomized clinical trial was conducted on patients of both sexes admitted to the Intensive Care Unit (ICU) of the Poison Control Center at Ain Shams University Hospital (PCC-ASUH) with acute OP toxicity during the period from the beginning of August 2022 to the end of July 2023. According to the Peradeniya score, Group I consisted of 48 patients (52%) with moderate OP poisoning, and Group II consisted of 44 patients (48%) with severe OP poisoning. Patients in the moderate group were assigned to receive either standard treatment (Group Ia, = 24) or standard treatment plus FFP (Group Ib, = 24). In addition, patients in the severe group were assigned to receive either standard treatment (Group IIa, = 22) or standard treatment plus FFP (Group IIb, = 22). A total of 46 patients received FFP transfusion. The authors demonstrated that the early use of a total of nine packs of FFP (250 mL each) over three consecutive days significantly reduced the total doses of atropine and oximes, the total hospitalization period, and the requirement for mechanical ventilation in patients with OP poisoning, both in the moderate and severe groups.
Topics: Humans; Female; Male; Plasma; Organophosphate Poisoning; Adult; Middle Aged; Single-Blind Method; Prospective Studies; Blood Component Transfusion; Young Adult; Antidotes
PubMed: 38861017
DOI: 10.1177/09603271241260655 -
Organic Letters Jun 2024The reactions of -isomers and -isomers usually are different in consideration of the regioselectivity of chemoselectivity. The syntheses of -isomers are not feasible in...
The reactions of -isomers and -isomers usually are different in consideration of the regioselectivity of chemoselectivity. The syntheses of -isomers are not feasible in many cases. The energy transfer (EnT) /-photoisomerization might yield the -isomers. In this work, was proven to be an EnT photocatalyst for the → -isomerization of C-C or C-N double bonds. The transformations of in situ generated -isomers of oximes and stilbenes consequently afforded the desired reversed Beckmann rearrangement products and phenanthrenes, respectively.
PubMed: 38856646
DOI: 10.1021/acs.orglett.4c01715 -
ACS Organic & Inorganic Au Jun 2024The synthesis of selenofunctionalized oxazolines and isoxazolines from -allyl benzamides and unsaturated oximes with diselenides was studied by utilizing a continuous...
The synthesis of selenofunctionalized oxazolines and isoxazolines from -allyl benzamides and unsaturated oximes with diselenides was studied by utilizing a continuous flow electrochemical approach. At mild reaction conditions and short reaction times of 10 min product yields of up to 90% were achieved including a scale-up reaction. A broad substrate scope was studied and the reaction was shown to have a wide functional group tolerance.
PubMed: 38855333
DOI: 10.1021/acsorginorgau.4c00008 -
Angewandte Chemie (International Ed. in... Jun 2024Nitrogen oxides (NOx) are major environmental pollutants and to neutralize this long-term environmental threat, new catalytic methods are needed. Although there are...
Nitrogen oxides (NOx) are major environmental pollutants and to neutralize this long-term environmental threat, new catalytic methods are needed. Although there are biological denitrification processes involving four different enzymatic reactions to convert nitrate (NO3-) to dinitrogen (N2), it is unfortunately difficult to apply in industry due to the complexity of the processes. In particular, nitrate is difficult to functionalize because of its chemical stability. Thus, there is no organometallic catalysis to convert nitrate to useful chemicals. In this article, we present that a nickel pincer complex is effective as a bifunctional catalyst to stepwise deoxygenate NO3- by carbonylation and further to C-N coupling. By using this nickel catalysis, nitrate salts can be selectively transformed into various oximes (>20 substrates) with excellent conversion (>90%). Here, we demonstrate for the first time that the highly inert nitrate ion can be functionalized to produce useful chemicals by a new organonickel catalysis. Our results show that the NOx conversion and utilization (NCU) technology is a successful pathway for environmental restoration coupled with value-added chemical generation.
PubMed: 38853142
DOI: 10.1002/anie.202408457 -
The Journal of Physical Chemistry. A Jun 2024The structure of samoquasine A has long been a subject of controversy, which was resolved only upon its successful total synthesis. We examined the structures of the...
The structure of samoquasine A has long been a subject of controversy, which was resolved only upon its successful total synthesis. We examined the structures of the associated compounds using the state-of-the-art SVM-M protocol. The method accurately discriminated all putative structures historically attributed to samoquasine A from a pool of 48 isomeric structures, confirming that samoquasine A is indeed identical to perlolidine. Furthermore, by applying the SVM-M protocol to an additional pool of 67 isomeric structures, we successfully assigned a yet unknown natural product, initially misidentified as perlolidine, as a novel oxime, ()-3-cyclopenta[]quinolin-3-one oxime, representing the first reported cyclone oxime-quinoline natural product.
PubMed: 38850258
DOI: 10.1021/acs.jpca.4c02916 -
Nature Communications Jun 2024Farmers from South Asian countries spray insecticides without protective gear, which leads to insecticide exposure through dermal and nasal routes. Acetylcholinesterase...
Oxime-functionalized anti-insecticide fabric reduces insecticide exposure through dermal and nasal routes, and prevents insecticide-induced neuromuscular-dysfunction and mortality.
Farmers from South Asian countries spray insecticides without protective gear, which leads to insecticide exposure through dermal and nasal routes. Acetylcholinesterase plays a crucial role in controlling neuromuscular function. Organophosphate and carbamate insecticides inhibit acetylcholinesterase, which leads to severe neuronal/cognitive dysfunction, breathing disorders, loss of endurance, and death. To address this issue, an Oxime-fabric is developed by covalently attaching silyl-pralidoxime to the cellulose of the fabric. The Oxime-fabric, when stitched as a bodysuit and facemask, efficiently deactivates insecticides (organophosphates and carbamates) upon contact, preventing exposure. The Oxime-fabric prevents insecticide-induced neuronal damage, neuro-muscular dysfunction, and loss of endurance. Furthermore, we observe a 100% survival rate in rats when repeatedly exposed to organophosphate-insecticide through the Oxime-fabric, while no survival is seen when organophosphate-insecticide applied directly or through normal fabric. The Oxime-fabric is washable and reusable for at least 50 cycles, providing an affordable solution to prevent insecticide-induced toxicity and lethality among farmers.
Topics: Animals; Insecticides; Rats; Oximes; Male; Pralidoxime Compounds; Textiles; Cholinesterase Inhibitors; Acetylcholinesterase; Occupational Exposure; Carbamates; Organophosphates; Administration, Intranasal
PubMed: 38844466
DOI: 10.1038/s41467-024-49167-3 -
Life Science Alliance Aug 2024Targeted therapies against mutant BRAF are effectively used in combination with MEK inhibitors (MEKi) to treat advanced melanoma. However, treatment success is affected...
Targeted therapies against mutant BRAF are effectively used in combination with MEK inhibitors (MEKi) to treat advanced melanoma. However, treatment success is affected by resistance and adverse events (AEs). Approved BRAF inhibitors (BRAFi) show high levels of target promiscuity, which can contribute to these effects. The blood vessel lining is in direct contact with high plasma concentrations of BRAFi, but effects of the inhibitors in this cell type are unknown. Hence, we aimed to characterize responses to approved BRAFi for melanoma in the vascular endothelium. We showed that clinically approved BRAFi induced a paradoxical activation of endothelial MAPK signaling. Moreover, phosphoproteomics revealed distinct sets of off-targets per inhibitor. Endothelial barrier function and junction integrity were impaired upon treatment with vemurafenib and the next-generation dimerization inhibitor PLX8394, but not with dabrafenib or encorafenib. Together, these findings provide insights into the surprisingly distinct side effects of BRAFi on endothelial signaling and functionality. Better understanding of off-target effects could help to identify molecular mechanisms behind AEs and guide the continued development of therapies for BRAF-mutant melanoma.
Topics: Proto-Oncogene Proteins B-raf; Humans; Protein Kinase Inhibitors; Melanoma; Signal Transduction; Vemurafenib; Oximes; Sulfonamides; Endothelium, Vascular; Imidazoles; Endothelial Cells; MAP Kinase Signaling System; Carbamates; Human Umbilical Vein Endothelial Cells; Cell Line, Tumor; Mutation
PubMed: 38839106
DOI: 10.26508/lsa.202402671