Synthetic Derivatives Research Articles

Effective and sustainable removal of Pb2+ ions from wastewater by a new synthetic bis-thiosemicarbazone derivative immobilized in amberlite XAD-2: Kinetic, isotherm and thermodynamic aspects

ABSTRACT A new composite material, named TSC/AXAD-2, was developed by incorporating a bis-thiosemicarbazone derivative (TSC) into Amberlite XAD-2 to extract Pb2+ ions from wastewater. The new composite was characterized using XPS, TGA, FTIR, BET, EDX, 1H-NMR, 13C-NMR, and GC-MS analyses. The sorption parameters, such as pH value of media, equilibrium time, initial Pb2+ ion concentration, composite dose, temperature, and eluting agents, were methodically optimized. The utmost adsorption capacity is 45.3 mg.g−1; it was achieved at pH value of of 5.5, 15 min of agitation, room temperature, and initial concentration of 200 mg.L−1 Pb2+ ions. The isotherm studies revealed that the adsorption process closely matches the Langmuir model, with a theoretical retention capacity of 46.12 mg.g−1. Furthermore, kinetic modeling using the pseudo-first-order accurately depicted the adsorption of Pb2+ ions. The thermodynamic study suggested that the adsorption process is exothermic, spontaneous, and more favorable at lower temperatures. The desorption of Pb2+ ions from the loaded composite was conducted with 1.0 M of either HCl or HNO3. The TSC/AXAD-2 composite successfully met WHO and FAO guidelines for removal of Pb2+ ions from wastewater before its discharge into the marine environment.

Pharmacogenomics of 3,4-Methylenedioxymethamphetamine (MDMA): A Narrative Review of the Literature.

3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative with notable psychoactive properties and emerging therapeutic potential, particularly for treating post-traumatic stress disorders (PTSD) and substance use disorders. However, its use remains controversial due to inter-individual variability influenced by both environmental and genetic factors. In this context, pharmacogenomics could play a crucial role in guiding MDMA treatment by identifying individuals with genetic predispositions affecting their response to MDMA. Tailoring treatment plans based on individual's genetic makeup may enhance therapeutic outcomes and minimize adverse effects, leading to safer and more effective use of MDMA in clinical settings. Literature analysis reveals that the influence of genetic variants within genes encoded for enzymes involved in MDMA metabolism and/or pharmacodynamics (PD) targets have been relatively under-investigated in humans. Some studies have pointed out associations between MDMA-induced effects and polymorphisms. For example, the catechol-O-methyltransferase (COMT) Val158Met polymorphism has been associated with cognitive and cardiovascular MDMA-induced effects. Similarly, polymorphisms in the serotonin-linked promoter region (5HTTLPR) have been associated with several MDMA-induced adverse effects including mood disorders. However, despite these findings, only a few associations have been highlighted. Furthermore, some genes encoded for MDMA targets have been only poorly investigated, representing a significant research gap. These observations underscore the need for large-scale, controlled pharmacogenomics studies focusing on a broad panel of genes involved into MDMA pharmacokinetics and PD. Such studies could provide critical insights for optimizing MDMA's therapeutic use and minimizing its risks.

Novel coumarin-6-sulfonamide-chalcone hybrids as glutathione transferase P1-1 inhibitors.

Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.

TET3-overexpressing macrophages promote endometriosis.

Endometriosis is a debilitating, chronic inflammatory disease affecting ~10% of reproductive age women worldwide with no cure. While macrophages have been intrinsically linked to the pathophysiology of endometriosis, targeting them therapeutically has been extremely challenging due to their high heterogeneity and because these disease-associated macrophages (DAMs) can be either pathogenic or protective. Here, we reported identification of pathogenic macrophages characterized by TET3 overexpression in human endometriosis lesions. We showed that factors from the disease microenvironment upregulated TET3 expression transforming macrophages into pathogenic DAMs. TET3 overexpression stimulated pro-inflammatory cytokine production via a feedback mechanism involving inhibition of let-7 miRNA expression. Remarkably, these cells relied on TET3 overexpression for survival, hence vulnerable to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, triggered TET3 degradation both in human and mouse macrophages. This degradation was dependent on a VHL E3 ubiquitin ligase whose expression was also upregulated in TET3-overexpressing macrophages. Furthermore, depleting TET3-overexpressing macrophages either through myeloid-specific Tet3 ablation or using Bobcat339 strongly inhibited endometriosis progression in mice. Our results defined TET3-overexpressing macrophages as key pathogenic contributors to and attractive therapeutic targets for endometriosis. Our findings may also be applicable to other chronic inflammatory diseases where DAMs have important roles.

One-Pot Syntheses and Enzyme Inhibition Studies of New C-28 Ester Derivatives of Betulinic Acid

Abstract: Betulinic acid and its various synthetic derivatives have been reported to possess diverse biological activities and some of these may serve as useful therapeutic agents for a variety of human disorders. In this perspective, we have now developed convenient one-pot syntheses of new C-28 esters (2-7) of betulinic acid by esterification of the carboxylic moiety of betulinic acid (1) with various alkylating agents. All the target compounds were subjected to enzyme inhibition studies to ascertain their possible therapeutic utility. Compound 5 showed very potent lipoxygenase inhibitory activity with an IC50 value of 13.2 μM, being much lower than the IC50 value of 22.4 μM of baicalein, which was used as the standard. Butulinic acid itself and compound 6 also showed significant inhibitory potential (IC50: 32.4 and 25.1 μM) against the same enzyme. The activities of both compounds 5 and 6 have been justified by intensive docking studies. Compounds 2 and 3 exhibited substantial inhibition (IC50: 18.4 and 21.5 μM) against the enzyme butrylcholinesterase, compared to serine used as the standard (IC50: 7.8 μM).

3,3-Dibromoflavanone, a synthetic flavonoid derivative for pain management with antidepressant-like effects and fewer side effects than those of morphine in mice

In the pursuit of new lead compounds with fewer side effects than opioids, the novel synthetic phytochemical core, 3,3-dibromoflavanone (3,3-DBF), has emerged as a promising candidate for pain management. Acute assays demonstrated dose-dependent central and peripheral antinociceptive activity of 3,3-DBF through the μ-opioid receptor. This study aimed to explore repeated administration effects of 3,3-DBF in mice and compare them with morphine.Mice were treated with 3,3-DBF (30 mg/kg), morphine (6 mg/kg), or vehicle for 10 days, alongside single-treatment groups. Unlike morphine, 3,3-DBF demonstrated antinociceptive effects in the hot plate test without inducing tolerance. Locomotor activity and motor coordination tests (evaluated through the inverted screen and rotarod tests) revealed no significant differences between the 3,3-DBF-treated and control groups. The gastrointestinal transit assay indicated that 3,3-DBF did not induce constipation, in contrast to morphine. Furthermore, withdrawal signs assessed with the Gellert-Holtzman scale were not comparable to morphine. Additionally, 3,3-DBF exhibited antidepressant-like activity, reducing immobility time in the forced swimming and tail suspension tests, akin to imipramine.In summary, 3,3-DBF demonstrated antinociceptive effects without inducing tolerance or dependence and exhibited antidepressant properties. These findings highlight the potential of 3,3-DBF as a promising therapeutic agent for pain management and its comorbidities, offering advantages over morphine by minimizing side effects.

Synthesis of Isatin-derived Heterocycles with Promising Anticancer Activities.

Isatin or 1H-indole-2,3-dione skeleton has been playing a significant role in drug de-sign and development. Isatin itself and many of its derivatives are widely distributed in naturally occurring bioactive compounds. Various synthetic isatin derivatives were found to possess a broad range of significant pharmacological efficacies especially anti-cancer activity against a wide variety of cancer cell lines. Interestingly, on a few occasions, some isatin-derived scaffolds were reported as more potent than the tested reputed drug molecules. As a result, isatin-derived compounds have been gaining significant attention in cancer-based drug developments. In this re-view, we have summarized literature reported during the last two decades related to the synthesis of structurally diverse isatin-derived scaffolds with promising anti-cancer activities.

Heterologous Expression of Epoxomicin in Escherichia coli.

Epoxomicin is an epoxyketone proteasome inhibitor with synthetic derivatives approved or under investigation for treatment of multiple myeloma. To leverage the advantages of Escherichia coli as a rapidly growing and readily engineered host for the production of epoxomicin and analogues, we expressed codon-optimized versions of the epoxomicin biosynthetic genes, epxD, epxE, and epxF. Epoxomicin was detected, but the major product was a ketone resulting from α,β-keto acid precursor decarboxylation. Epoxomicin yield was improved by altering the copy numbers of each gene and creating a fusion of epxE and epxF. Our optimized system offers promise for efficient engineering and biosynthesis of improved epoxomicin analogues.

Tyrosinase Inhibition and Antimelanogenic Effects of Resorcinol-Containing Compounds.

Tyrosinases (TYRs) are copper-containing metalloenzymes present in a large diversity of species. In human, hTYR is responsible for pivotal steps in melanogenesis, catalysing the oxidation of l-tyrosine to l-DOPA and further to dopaquinone. While numerous TYR inhibitors have been reported, polyphenolic compounds tend to dominate the literature. However, many of these compounds, particularly monophenols and catechols, have been identified as alternative substrates rather than true inhibitors, given their structural similarity to natural substrates. Resorcinol-containing compounds have emerged as promising candidates to address this challenge, as the meta-dihydroxy moiety in resorcinol demonstrates resistance to TYR-mediated oxidation, while retaining the favourable interactions with copper ions provided by the hydroxy groups. Although their precise mechanism of action remains debated, resorcinol derivatives have yielded some of the most active compounds against isolated mushroom and human TYRs, as well as clinically used dermocosmetic agents like rucinol and thiamidol, which exhibited very promising effects in patients with facial melasma. This review outlines the development of resorcinol-containing TYR inhibitors, categorized by scaffold type, ranging from simple alkyl analogues to intricate synthetic derivatives. Mechanistic insights about the resorcinol-TYR interaction are also presented and debated.

Abstract We102: Synthetic N-Acylurea Derivative Reduces Angiogenesis in Human Endothelial Cells by Talin Modulation

Talin is a focal adhesion protein that activates integrins and recruits other focal adhesion proteins. Talin regulates the interactions between integrins and the extracellular matrix, which are critical for endothelial cells during angiogenesis. In this study, we successfully synthesized a novel talin modulator, N-((2-(1H-indol-3-yl)ethyl)carbamoyl)-2-(benzo[d][1,3]dioxol-5-yloxy)acetamide, referred to as KCH-1521. KCH-1521 was determined to bind talin and modulate downstream signaling molecules of talin. After 24 hrs of treatment, KCH-1521 changed the cell morphology of HUVECs and reduced focal adhesion protein expression including vinculin and paxillin. Talin downstream signaling is regulated via FAK, AKT, and ERK pathways, however, treatment with KCH-1521 decreased phosphorylation of FAK, AKT, and ERK, leading to a reduction of cell proliferation, survival, and angiogenesis. Interestingly, the expression of various angiogenic genes was significantly decreased after treatment with KCH-1521. Also, in vitro tube forming assay revealed that KCH-1521 reduced angiogenic networks in a time-dependent manner. To investigate the reversibility of its effects, KCH-1521 was removed after treatment. HUVECs recovered their morphology through rearrangement of the cytoskeleton and the expression of angiogenic genes was also recovered. By further optimization and in vivo studies of KCH-1521, a novel drug of talin modulation could be used to achieve therapeutic anti-angiogenesis for vascular diseases and cancers.

Molecular Modeling of some 1,3,4-Oxadiazole Derivatives as EGFR Inhibitors for the Treatment of Cancer

Background: Cancer is a group of illnesses characterised by the impartial increase and unfolding of somatic cells. A variety of natural compounds, such as curcumin, zingiberine and their composites, and synthetic organic derivatives of imidazole, benzothiazole, oxadiazole, quinazoline etc., have been developed as anticancer agents. But many of these show various side effects, drug resilience, and toxicity to the normal cells of the host body. Therefore, there is still demand to develop new synthetic derivatives to improve their pharmacological profile. Objective: The Aim of this study is to understand the binding mode and to check the drug likeliness of numerous 1,3,4-oxadiazole derivatives as EGFR inhibitors for the treatment of cancer. The objective of the study is to screen newly designed derivatives of 1,3,4-oxadiazole using molecular docking and ADMET studies as EGFR inhibitors. Methods: In silico docking studies were performed using AutoDockVina software, and compounds were further studied for ADME and toxicity using SwissADME and pkCSM software, respectively. Results: Considering the docking results, pharmacokinetic behaviour and toxicity profile, eight derivatives (derivatives 2,3,4,5,10,13,16, and 17) showed potential as EGFR inhibitors. Conclusion: Compounds 2 and 3 showed the highest binding affinity in the pocket of EGFR and also displayed a better pharmacokinetic profile. Therefore, these derivatives can be used in the management of cancer and can be taken further for wet-lab studies.

Investigation of Anti-inflammatory and Antioxidant Activities of Promising 1,4,5-Trisubstituted Pyrazoles Derivatives of Chalcone Ditosylates

Patients suffering from chronic pain and inflammatory disorders need novel COX-2 inhibitors to be developed with minimum toxicity to the kidneys, heart, and gastrointestinal tract and with excellent anti-inflammatory activity. The current study centers on an array of 1,4,5-trisubstituted pyrazoles produced via the reaction of ditosylates of chalcones with hydrochloride salt of phenylhydrazine. Chalcone was reacted with HTIB to produce a variety of derivatives of α, β chalcone ditosylates. Phenylhydrazine hydrochloride treatment of these chalcone ditosylates produced distinct 1,4,5-trisubstituted pyrazoles. The conversion process is mediated by 1,2-aryl migrations. IR, 1NMR, and elemental analysis were used to characterize the compounds after they had been purified by recrystallization. Using ascorbic acid as a reference, the DPPH (1,1-diphenyl-2-picrylhydrazyl) technique was used to assess the compounds' in vitro antioxidant activity. The paw edema technique caused by Carrageenan was utilized to assess the compounds' in vivo anti-inflammatory properties. The standard medication used was diclofenac sodium. A plethysmograph was used to measure the volume of the rats' paws. When compared to the standard, the compounds V5D5PH5 and V7D7PH7 showed modest antioxidant activity. When the synthetic pyrazoles were examined for their in vivo anti-inflammatory properties, substances V4D4PH4 and V7D7PH7 outperformed the reference. Here, we attempted to create new, safe, and effective drugs for the treatment of inflammatory disorders and pain by utilizing synthetic pyrazole moiety derivatives. Simple experimentation is used in the proposed study to improve pharmacological activity and yields. In the near future, chalcone ditosylate derivatives will be a powerful tool for selective modification.

Verazine biosynthesis from simple sugars in engineered Saccharomyces cerevisiae

Steroidal alkaloids are FDA-approved drugs (e.g., Zytiga) and promising drug candidates/leads (e.g., cyclopamine); yet many of the ≥697 known steroidal alkaloid natural products remain underutilized as drugs because it can be challenging to scale their biosynthesis in their producing organisms. Cyclopamine is a steroidal alkaloid produced by corn lily (Veratrum spp.) plants, and it is an inhibitor of the Hedgehog (Hh) signaling pathway. Therefore, cyclopamine is an important drug candidate/lead to treat human diseases that are associated with dysregulated Hh signaling, such as basal cell carcinoma and acute myeloid leukemia. Cyclopamine and its semi-synthetic derivatives have been studied in (pre)clinical trials as Hh inhibitor-based drugs. However, challenges in scaling the production of cyclopamine have slowed efforts to improve its efficacy and safety profile through (bio)synthetic derivatization, often limiting drug development to synthetic analogs of cyclopamine such as the FDA-approved drugs Odomzo, Daurismo, and Erivedge. If a platform for the scalable and sustainable production of cyclopamine were established, then its (bio)synthetic derivatization, clinical development, and, ultimately, widespread distribution could be accelerated. Ongoing efforts to achieve this goal include the biosynthesis of cyclopamine in Veratrum plant cell culture and the semi-/total chemical synthesis of cyclopamine. Herein, this work advances efforts towards a promising future approach: the biosynthesis of cyclopamine in engineered microorganisms. We completed the heterologous microbial production of verazine (biosynthetic precursor to cyclopamine) from simple sugars (i.e., glucose and galactose) in engineered Saccharomyces cerevisiae (S. cerevisiae) through the inducible upregulation of the native yeast mevalonate and lanosterol biosynthetic pathways, diversion of biosynthetic flux from ergosterol (i.e., native sterol in S. cerevisiae) to cholesterol (i.e., biosynthetic precursor to verazine), and expression of a refactored five-step verazine biosynthetic pathway. The engineered S. cerevisiae strain that produced verazine contains eight heterologous enzymes sourced from seven different species. Importantly, S. cerevisiae-produced verazine was indistinguishable via liquid chromatography-mass spectrometry from both a commercial standard (Veratrum spp. plant-produced) and Nicotiana benthamiana-produced verazine. To the best of our knowledge, this is the first report describing the heterologous production of a steroidal alkaloid in an engineered yeast. Verazine production was ultimately increased through design-build-test-learn cycles to a final titer of 83 ± 3 μg/L (4.1 ± 0.1 μg/g DCW). Together, this research lays the groundwork for future microbial biosynthesis of cyclopamine, (bio)synthetic derivatives of cyclopamine, and other steroidal alkaloid natural products.

Enhancing the efficacy of antimicrobial photodynamic therapy through curcumin modifications.

Curcumin serves as a photosensitizer (PS) in the context of microbial inactivation when subjected to light exposure, to produce reactive oxygen species, which exhibit efficacy in eradicating microorganisms. This remarkable property underscores the growing potential of antimicrobial photodynamic therapy (aPDT) in the ongoing fight against bacterial infections. Considering this, we investigate the efficacy of various invitro curcumin formulations within a PDT protocol designed to target Staphylococcus aureus. Specifically, we conduct a comparative analysis involving synthetic curcumin (Cur-Syn) and curcumin derivatives modified with chlorine (Cl), selenium (Se), and iodine (I) (Cur-Cl, Cur-Se, Cur-I). To assess the impact of aPDT, we subject S. aureus to incubation with curcumin, followed by irradiation at 450 nm with energy doses of 3.75, 7.5, and 15 J/cm2. Our investigation encompasses an evaluation of PS uptake and photobleaching across the various curcumin variants. Notably, all three modifications (Cur-Cl, Cur-Se, Cur-I) induce a significant reduction in bacterial viability, approximately achieving a 3-log reduction. Interestingly, the uptake kinetics of Cur-Syn and Cur-Se exhibit similarities, reaching saturation after 20 min. Our findings suggest that modifications to curcumin have a discernible impact on the photodynamic properties of the PS molecule.

Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms.

Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.

Mephedrone concentrations in clinical intoxications and fatal cases: a systematic review.

Mephedrone, a ring-substituted synthetic cathinone derivative, gained popularity as a recreational drug in the late 2000s. Reports of fatalities related to mephedrone use have emerged with varying concentrations of blood mephedrone upon forensic investigations. This study aims to evaluate the existing literature on mephedrone concentrations in instances of clinical intoxication and fatal cases. We comprehensively searched electronic databases, including Web of Science, PubMed, Embase, and the Cochrane Library, from inception to July 26, 2023. We selected case reports or case series of mephedrone intoxication presented with individual blood mephedrone concentration. Patient demographics, clinical characteristics, blood mephedrone concentrations, and outcomes were extracted for analysis. 77 cases from 14 case reports and 6 case series were identified for review. There were 34 deaths and 43 non-fatal intoxication cases. The median patient's age was 24years (IQR: 10), and 91.4% were male. Forty-five of the 63 cases (71.4%) were reported with alcohol or other illicit drugs detected. The median blood mephedrone concentration was 0.37mg/L (IQR: 1.09mg/L). Death cases were older than non-fatal cases (median = 30 vs. 22years, p = 0.029). The median blood mephedrone concentration was higher in death cases (1.30mg/L vs. 0.12mg/L, p < 0.0001). Blood mephedrone concentration in dead patients is approximately 11 times higher than in non-fatal cases. This finding could serve as a stepping stone to the diagnosis of concentrations in clinical poisoning cases and deaths, especially in the treatment of poisoning patients. In more extensive prospective studies, further research is necessary to establish a standardized, real-time available methodology and validate the predictive value of mephedrone concentrations in the prognostic value of mephedrone concentrations.

Biological Profile of Synthetic and Natural Indole Derivatives: Paving New Paths in Cancer Treatment

Biological Profile of Synthetic and Natural Indole Derivatives: Paving New Paths in Cancer Treatment

Natural products as promising modulators of breast cancer immunotherapy.

Breast cancer (BC) is the most common malignancy among women and is considered a major global health challenge worldwide due to its high incidence and mortality rates. Treatment strategies for BC is wide-ranging and include surgery, radiotherapy, chemotherapy, targeted hormonal therapy and immunotherapy. Immunotherapy has gained popularity recently and is often integrated as a component of personalized cancer care because it aims to strengthen the immune system and enable it to recognize and eradicate transformed cells. It has fewer side-effects and lower toxicity than other treatment strategies, such as chemotherapy. Many natural products are being investigated for a wide range of therapeutic pharmacological properties, such as immune system modulation and activity against infection, auto-immune disease, and cancer. This review presents an overview of the major immune response-related pathways in BC, followed by detailed explanation of how natural compounds can act as immunomodulatory agents against biomolecular targets. Research has been carried out on many forms of natural products, including extracts, isolated entities, synthetic derivatives, nanoparticles, and combinations of natural compounds. Findings have shown significant regulatory effects on immune cells and immune cytokines that lead to immunogenic cancer cell death, as well as upregulation of macrophages and CD+8 T cells, and increased natural killer cell and dendritic cell activity. Natural products have also been found to inhibit some immuno-suppressive cells such as Treg and myeloid-derived suppressor cells, and to decrease immunosuppressive factors such as TGF-β and IL-10. Also, some natural compounds have been found to target and hinder immune checkpoints such as PD-L1.

Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3β inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3β/Nrf2 pathway

BackgroundAlzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive deficits. Although the pathogenesis of AD is unclear, oxidative stress has been implicated to play a dominant role in its development. The flavonoid isoorientin (ISO) and its synthetic derivatives TFGF-18 selectively inhibit glycogen synthase kinase-3β (GSK-3β), a potential target of AD treatment. PurposeTo investigate the neuroprotective effect of TFGF-18 against oxidative stress via the GSK-3β pathway in hydrogen peroxide (H2O2)-induced rat pheochromocytoma PC12 cells in vitro and scopolamine (SCOP)-induced AD mice in vivo. MethodThe oxidative stress of PC12 cells was induced by H2O2 (600 μM) and the effects of TFGF-18 (2 and 8 μM) or ISO (12.5 and 50 μM) were observed. The AD mouse model was induced by SCOP (3 mg/kg), and the effects of TFGF-18 (2 and 8 mg/kg), ISO (50 mg/kg), and donepezil (DNP) (3 mg/kg) were observed. DNP, a currently accepted drug for AD was used as a positive control. The neuronal cell damages were analyzed by flow cytometry, LDH assay, JC-1 assay and Nissl staining. The oxidative stress was evaluated by the detection of MDA, SOD, GPx and ROS. The level of ACh, and the activity of AChE, ChAT were detected by the assay kit. The expressions of Bax, Bcl-2, caspase3, cleaved-caspase3, p-AKT (Thr308), AKT, p-GSK-3β (Ser9), GSK-3β, Nrf2, and HO-1, as well as p-CREB (Ser133), CREB, and BDNF were analyzed by western blotting. Morris water maze test was performed to analyze learning and memory ability. ResultsTFGF-18 inhibited neuronal damage and the expressions of Bax, caspase3 and cleaved-caspase3, and increased the expression of Bcl-2 in vitro and in vivo. The level of MDA and ROS were decreased while the activities of SOD and GPx were increased by TFGF-18. Moreover, TFGF-18 increased the p-AKT, p-GSK-3β (Ser9), Nrf2, HO-1, p-CREB, and BDNF expression reduced by H2O2 and SCOP. Meanwhile, MK2206, an AKT inhibitor, reversed the effect of TFGF-18 on the AKT/GSK-3β pathway. In addition, the cholinergic system (ACh, ChAT, and AChE) disorders were retrained and the learning and memory impairments were prevented by TFGF-18 in SCOP-induced AD mice. ConclusionsTFGF-18 protects against neuronal cell damage and cognitive impairment by inhibiting oxidative stress via AKT/GSK-3β/Nrf2 pathway.

Tranexamic acid-induced seizures in postpartum patients

Introduction: Tranexamic acid has found extensive application in obstetrics to prevent and treat postpartum hemorrhage (PPH). This case report investigated an infrequent incidence in which seizures were caused by the administration of tranexamic acid. Even though tranexamic acid is generally regarded as safe, it has been associated with the infrequent yet serious side effects of tranexamic acid-induced seizures. This case report was aimed at investigating the infrequent incidence of tranexamic acid-induced seizures in postpartum patients. Case: It was reported that a woman who was 40 weeks pregnant suffered from postpartum seizures after delivery via cesarean section. These seizures occurred after tranexamic acid was administered to treat postpartum hemorrhage (PPH) caused by uterine rupture, which was accompanied by hypocalcemia. Despite not having a history of epilepsy, preeclampsia, or hypertension, the electrocardiogram (EKG) showed a prolongation of the QT interval. A comprehensive diagnostic evaluation, which involved a CT scan of the head and a D-dimer examination, was conducted, revealing no abnormalities. Discussion: Tranexamic acid, a synthetic derivative of lysine, acts as a competitive inhibitor of plasminogen activation, thereby inhibiting the breakdown of fibrin clots.