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The rapid development of messenger RNA (mRNA) vaccines formulated with lipid nanoparticles (LNPs) has contributed to control of the COVID-19 pandemic. However, mRNA vaccines have raised concerns about their potential toxicity and clinical safety, including side effects, such as myocarditis, anaphylaxis, and pericarditis. In this study, we investigated the potential of trehalose glycolipids-containing LNP (LNP S050L) to reduce the risks associated with ionizable lipids. Trehalose glycolipids can form hydrogen bonds with polar biomolecules, allowing the formation of a stable LNP structure by replacing half of the ionizable lipids. The efficacy and safety of LNP S050L were evaluated by encapsulating the mRNA encoding the luciferase reporter gene and measuring gene expression and organ toxicity, respectively. Furthermore, mice immunized with an LNP S050L-formulated mRNA vaccine expressing influenza hemagglutinin exhibited a significant reduction in organ toxicity, including in the heart, spleen, and liver, while sustaining gene expression and immune efficiency, compared to conventional LNPs (Con-LNPs). Our findings suggest that LNP S050L, a trehalose glycolipid-based LNP, could facilitate the development of safe mRNA vaccines with improved clinical safety.

The reliability and efficiency of electrical power systems are critical for modern industries, which increasingly rely on electric machines and devices. However, power electronic converters add non-linear demands to the electric power distribution systems (EPDS), that can cause power quality (PQ) problems, which could harm electric devices. As a result, EPDS are pointed for the most effective and economical techniques to enhance PQ. Therefore, Dynamic Voltage Restorer (DVR) is employed to maintain voltage stability in modern EPDS. This study focuses on the application of Sliding Mode Control (SMC) in DVRs to protect against voltage dips, enhancing power system sustainability. It details the construction, operation, and control methods of DVRs, comparing the conventional PI-controller with SMC. The arctic puffin optimizer is utilized to get the optimum gains of the PI regulator, and at the same time, it is used to specify the optimal sliding surface required for SMC. A distribution system contains DVR is suggested and implemented utilizing Simulink/MATLAB. The simulation results of the DVR employing SMC and the conventional PI-controller demonstrate a marked improvement in voltage regulation and power quality. Specifically, the SMC-based DVR exhibited a reduction in voltage sag duration and magnitude by approximately 30 % compared to the PI-controller. Additionally, the total harmonic distortion (THD) in the load voltage was reduced by 25 %, indicating a significant enhancement in power quality. These improvements of the enhanced performance of the SMC-based DVR supports the seamless integration of renewable energy sources, which often introduce variability into the power grid.

The design of kinase inhibitors targeting the oncogenic kinase BCR-ABL constitutes a promising paradigm for treating chronic myeloid leukaemia (CML). Nevertheless, the efficacy of imatinib, the first FDA-approved targeted therapy for CML, is curbed by the emergence of resistance. Herein, we report the identification of the 2-methoxyphenyl ureidobenzothiazole AK-HW-90 (2b) as a potent pan-BCR-ABL inhibitor against imatinib-resistant mutants, particularly T315I. A concise array of six compounds 2a–f was designed based on our previously reported benzothiazole lead AKE-5l to improve its BCR-ABLT315I inhibitory activity. Replacing the 6-oxypicolinamide moiety of AKE-5l with o-methoxyphenyl and changing the propyl spacer with phenyl afforded 2a and AK-HW-90 (2b) with IC50 values of 2.0 and 0.65 nM against BCR-ABLT315I, respectively. AK-HW-90 showed superior anticancer potency to imatinib against multiple cancer cells (NCI), including leukaemia K-562. The obtained outcomes offer AK-HW-90 as a promising candidate for the treatment of CML and other types of cancer.

BCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABLT315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC50 values of < 0.5 nM, and 9 nM against BCR-ABLWT and BCR-ABLT315I, respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI50 < 10 nM, TGI = 154 nM). In addition, AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation.

A series of 6-ureido/amidocoumarins (5a–p and 7a–c) has been designed and synthesised to develop potent and isoform- selective carbonic anhydrase hCA XI and XII inhibitors. All coumarin derivatives were investigated for their CA inhibitory effect against hCA I, II, IX, and XII. Interestingly, target coumarins potently inhibited both tumour-related isoforms hCA IX (KIs: 14.7–82.4 nM) and hCA XII (KIs: 5.9–95.1 nM), whereas the cytosolic off-target hCA I and II isoforms have not inhibited by all tested coumarins up to 100 μM. These findings granted the target coumarins an excellent selectivity profile towards both hCA IX and hCA XII isoforms, supporting their development as promising anticancer candidates. Moreover, all target molecules were evaluated for their anticancer activities against HCT-116 and MCF-7 cancer cells. The 3,5-bis-trifluoromethylphenyl ureidocoumarin 5i, exerted the best anticancer activity. Overall, ureidocoumarins, particularly compound 5i, could serve as a promising prototype for the development of potent anticancer CAIs.

Abstract The major objective of this study was to examine the viability of using 5, 10, or 15 mass% of Activated Alum Sludge waste (AAS) instead of Ordinary Portland Cement (OPC) as a pozzolanic ingredient in concrete. This fundamental inquiry framed the investigation and OPC-AAS-hardened composites were studied to see whether they may benefit from inexpensive nanocomposites in terms of improved physical properties, mechanical strength, and resistance to heat and flame. The investigation set out to see how inexpensive nanocomposite might be put to use and the nanoparticles of CuFe2O4 spinel with an average size of less than 50 nm were successfully manufactured. Many different OPC-AAS-hardened composites benefit from the addition of CuFe2O4 spinel, which increases the composites' resistance to fire and enhances their physicomechanical properties at roughly average curing ages. Synthesized CuFe2O4 spinel was shown to have desirable characteristics by TGA/DTG and XRD. By using these methods, we were able to identify a broad variety of hydration yields, including C–S–Hs, C–A–S–Hs, C–F–S–Hs, and Cu–S–Hs, that enhance the physicomechanical properties and thermal resistivity of OPC-AAS-hardened composites as a whole. The composite material comprising 90% OPC, 10% AAS waste, and 2% CuFe2O4 has several positive economic and environmental outcomes.

Abstract Background Oral cancer, one of the most common cancers, has unimproved 5-years survival rate in the last 30 years and the chemo/radiotherapy-associated morbidity. Therefore, intervention strategies that evade harmful side effects of the conventional treatment modalities are of need. Herbal therapy as a complementary preventive/therapeutic modality has gained attention. Curcumin is one of the herbal compounds possessing unique anticancer activity and luminescent optical properties. However, its low water solubility limits its efficacy. In contrast, curcumin at the nanoscale shows altered physical properties with enhancing bioavailability. Methods The current study evaluated the impact of nanocurcumin as an anti-oral cancer herbal remedy, comparing its efficacy against the native curcumin complement and conventional chemotherapeutic. An optimized polymeric-stabilized nanocurcumin was synthesized using the solvent-antisolvent precipitation technique. After assuring the solubility and biocompatibility of nanocurcumin, we determined its cytotoxic dose in treating the squamous cell carcinoma cell line. We then evaluated the anti-tumorigenic activity of the nano-herb in inhibiting wound closure and the cytological alterations of the treated cancer cells. Furthermore, the cellular uptake of the nanocurcumin was assessed depending on its autofluorescence. Results The hydrophilic optimized nanocurcumin has a potent cancerous cytotoxicity at a lower dose (60.8 µg/mL) than the native curcumin particles (212.4 µg/mL) that precipitated on high doses hindering their cellular uptake. Moreover, the nanocurcumin showed differential targeting of the cancer cells over the normal fibroblasts with a selectivity index of 4.5. With the confocal microscopy, the luminescent nanoparticles showed gradual nuclear and cytoplasmic uptake with apparent apoptotic cell death, over the fluorescent doxorubicin with its necrotic effect. Furthermore, the nanocurcumin superiorly inhibited the migration of cancer cells by -25%. Conclusions The bioavailable nanocurcumin has better apoptotic cytotoxicity. Moreover, its superior luminescence promotes the theranostic potentialities of the nano-herb combating oral cancer.

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Discoidin domain receptor 1 (DDR1) kinase has emerged as a promising target for cancer therapy, and selective DDR1 inhibitors have shown promise as effective therapeutic candidates. Herein, we have identified the first coumarin-based selective DDR1 inhibitors via repurposing of a recent series of carbonic anhydrase inhibitors. Among these, ureidocoumarins 3a, 3i, and 3q showed the best DDR1 inhibitory activities. The m-trifluoromethoxy phenyl member 3q potently inhibited DDR1 with an IC50 of 191 nM, while it showed less inhibitory activity against DDR2 (IC50 = 5080 nM). 3q also exhibited favorable selectivity in a screening platform with 23 common off-target kinases, including BCR-ABL. In the cellular context, 3q showed moderate antiproliferative effects, while 3i, with the third rank in DDR1 inhibition, exerted the best anticancer activity with sub-micromolar GI50 values over certain DDR1-dependent cell lines. Molecular docking and MD simulations disclosed the putative binding mode of this coumarin chemotype and provided insights for further optimization of this scaffold. The present findings collectively supported the potential improvement of ureidocoumarins 3i and 3q for cancer treatment.

Abstract Ultra-small gold nanoparticles (Au-NPs) “≤ 10 nm diameters” have potent biomedical applications. Hence, the present study aimed to greenly synthesize ultra-small gold nanoparticles using Egyptian propolis extract. Different biological activities, in vivo bio-distribution and acute toxicity study were assessed. Results revealed that, Egyptian propolis extract can successfully synthesize the highly pure and stable ultra-small Au-NPs with average diameter 7.8 nm. In vitro antimicrobial and antimycobacterial activities revealed the powerful effect of the prepared Au-NPs. Moreover, the cytotoxic effect on human cancer cell lines revealed the potent inhibition of the cancer cells’ proliferation with high reactive oxygen species-mediated apoptosis induction. In vivo bio-distribution and acute toxicity studies were performed (10 and 100 mg/kg doses) in male albino rats. The ultra-small Au-NPs showed low or no toxicity upon using the Au-NPs low dose. The mean area accumulation (%) of the Au-NPs was higher in the liver, kidney, and brain tissues (4.41, 2.96, and 0.3 times, respectively) treated with high Au-NPs dosage compared to those treated with the low dose. Surprisingly, Au-NP accumulation in brain tissue was observed in the glial cells only. Accordingly, the low dose (10 mg/kg) of Au-NPs can be used safely in a variety of biomedical applications.

The human lysine acetyltransferases KAT3A (CREBBP) and KAT3B (EP300) are essential enzymes in gene regulation in the nucleus. Their ubiquitous expression in metazoan cell types controls cell proliferation and differentiation during development. This comprehensive review delves into the biological roles of KAT3A and KAT3B in neurodevelopment, shedding light on how alterations in their regulation or activity can potentially contribute to a spectrum of neurodegenerative diseases (e.g., Huntington's and Alzheimer's). We explore the pathophysiological implications of KAT3 function loss in these disorders, considering their conserved protein domains and biochemical functions in chromatin regulation. The discussion also underscores the crucial role of KAT3 proteins and their substrates in supporting the integration of key cell signaling pathways. Furthermore, the narrative highlights the interdependence of KAT3-mediated lysine acetylation with lysine methylation and arginine methylation. From a cellular perspective, KAT3-dependent signal integration at subnuclear domains is mediated by liquid–liquid phase separation in response to KAT3-mediated lysine acetylation. The disruption of these finely tuned regulatory processes underscores their pathological roles in neurodegeneration. This review also points to the exciting potential for future research in this field, inspiring further investigation and discovery in the area of neurodevelopment and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Several molecular mechanisms contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD); however, the exact mechanism is not completely understood. Cyclic adenosine monophosphate (cAMP) is one of the most promising pathways that regulates various cellular functions including lipid and carbohydrate metabolism. cAMP induces gene transcription through phosphorylation of the transcription factor, cAMP response element-binding protein (CREB). The action of cAMP is tightly regulated by its level and repression. Among the repressors, Inducible cAMP Early Repressor (ICER) is the only inducible CRE-binding protein. The present study aimed to evaluate the role of hepatic CREB level in the development of experimental NAFLD model to clarify the pathogenesis of the disease. NAFLD 35 male Wistar rats fed a high fat diet for a period of 14 weeks were studied compared with 35 control rats fed a standard diet. Five fasting rats were sacrificed each 2 weeks intervals for a period of 14 weeks. Results NAFLD group revealed a remarkable duration—dependent elevation in cAMP and CREB levels in the liver tissue compared to control group (P value < 0.004, P value < 0.006, respectively). In contrast, ICER gene expression, as a dominant-negative regulator of CREB, was downregulated in the liver of NAFLD group compared to control group. We also demonstrated that CREB levels were positively correlated with liver function tests, and glucose homeostasis parameters. Conclusions Our results indicate that cAMP/CREB pathway provides an early signal in the progression to NAFLD representing a noninvasive biomarker that can early detect NAFLD and a promising therapeutic target for the treatment of the disease as well.

A new series of 3,4,5-trimethoxyphenyl thiazole pyrimidines has been synthesized and biologically evaluated for its in vitro anticancer activity. Compounds 4a, 4b, and 4h with substituted piperazine showed the best antiproliferative activity. In the NCI-60 cell line screening, compound 4b showed promising cytostatic activity against multiple cell lines. Notably, it elicited a GI value of 86.28% against the NSCL cancer cell line HOP-92 at a 10 μM dose. Compounds 4a and 4h at 10 μM showed promising GI values of 40.87% and 46.14% against HCT-116 colorectal carcinoma and SK-BR-3 breast cancer cell lines, respectively. ADME-Tox prediction of compounds 4a, 4b, and 4h revealed their acceptable drug-likeness properties. In addition, compounds 4a, 4b, and 4h showed a high probability of targeting kinase receptors via Molinspiration and Swiss TargetPrediction.

Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC50 of 0.71 μM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC50 = 1.11 μM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with Ki values of 0.21 and 0.28 μM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC50 of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC50 of 1.19–3.87 μM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (−11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood–brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases.