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Hana Saif Ali, Ephrem Engidawork Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, EthiopiaCorrespondence: Ephrem Engidawork, Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, P.O. Box 9086, Addis Ababa, Ethiopia, Email ephrem.engidawork@aau.edu.etBackground: The root bark of Carissa spinarum Linn. (Apocynaceae) is claimed to be used for the management of depression in Ethiopian folkloric medicine, and the crude extract has been reported to possess antidepressant-like activity in rodents.Objective: This study aimed to evaluate the antidepressant-like effect of different fractions of the root bark in rodents and the possible underlying mechanisms in rats.Methods: A 70% ethanol extract of the root bark was successively fractionated with n-butanol, ethyl acetate, and water. Animals of both sexes received 2% Tween 80, imipramine (30 mg/kg), or various doses (50, 100, 200 mg/kg) of the fractions. Duration of immobility was determined using the tail suspension test and the forced swim test. Locomotor activity was evaluated in the open field test. Serum corticosterone levels, total phenols, flavonoids, and alkaloids were determined. Preliminary mechanistic studies were also performed to explore possible mechanisms of action of the active fraction.Results: All fractions but the aqueous fraction significantly (p< 0.001) decreased the duration of immobility in both tests, with the ethyl acetate fraction being the most active. The locomotor test revealed that the activity was not due to non-specific psycho-stimulant effects. Serum corticosterone levels were reduced by both fractions, with the ethyl acetate fraction again being the most effective. Mechanistic studies showed the involvement of multiple neurotransmission systems, including adrenergic, dopaminergic and cholinergic as well as L-Arginine-NO-cGMP pathway. Higher contents of phenols (42.42 vs 29.8 mgGAE/g), flavonoids (12.43 vs 2.07 mgQE/g), and alkaloids (0.17 vs 0.07 mgATE/g) were found in the ethyl acetate than in the n-butanol fraction.Conclusion: The present findings collectively indicate that the ethyl acetate and n-butanol fractions are endowed with antidepressant-like activity due to the presence of phenols, flavonoids, and alkaloids, which are medium polar in nature.Keywords: depression, Carissa spinarum Linn, antidepressant-like activity, solvent fractions, possible mechanisms

Inappropriate prescribing reduces the quality of medical care and leads to a waste of resources. No study has been reported concerning rational drug use in United Arab Emirates, UAE, recently. Objectives: 1. assessing patterns of use and defining problems regarding the rational drug use. 2. Setting baseline situational analysis study for practices in the health care system relevant to drug use. Method: A descriptive pilot study, consisting of pharmacists, physicians and patients (100 of each of category) from four private hospitals, (12) medical clinics, (80) community pharmacies in addition to 150 prescriptions. A questionnaire of three sections was designed to include WHO indicators regarding patients, facility and prescribing patterns that are relevant to rational drug use was carried out in four emirates of the UAE in the period December 2008-Febreuary 2009.Results: Consultation and dispensing times were 10 (SD=2.75) min and 68 (SD=9.7) seconds, respectively. Average no. of drugs per prescription was (2.9 + 0.97), % of prescriptions using generic name (7.35%), % of antibiotic containing prescriptions (31.1%), % of injection containing prescriptions (2.9%), adherence to Standard Treatment Protocols (46%), adherence to the essential drug list (64%), patient’s knowledge of correct dosage (55%), adequately labeled drugs (45%), patient’s information (65%). Conclusions: Several areas of deficiency in rational drug use had been defined in the private sector through UAE that can be remedied through adopting several strategies such as adherence to national standard treatment guidelines and essential drug list based on treatments of choice, interaction between health care system and providing drugs information to consumers.

Hany SM Ali,1,2 Ahmed F Hanafy,3 Rawan Bafail,1 Hamad Alrbyawi,1 Marey Almaghrabi,1 Yaser M Alahmadi,4 Samar El Achy5 1Department of Pharmaceutics and Pharmaceutical Industries, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawwarah, Saudi Arabia; 2Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt; 3Research and Development Department, Al Andalous Pharmaceutical Industries, Giza, Egypt; 4Department of Pharmacy Practice, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawarah, 30001, Saudi Arabia; 5Department of Anatomical Pathology, Faculty of Medicine, University of Alexandria, Alexandria, EgyptCorrespondence: Hany SM Ali, Email hsali@taibahu.edu.sa, hafandy2000@yahoo.comBackground: Budesonide (BUD) is a BCS class II medication with poor water solubility and limited oral bioavailability. In this study, innovative solid self-microemulsifying drug delivery systems (BUD-SMEDDS) were developed for effective local management of distal ulcerative colitis (UC).Methods: Based on solubility and emulsification tests, the components of the self-microemulsifying drug delivery system (SMEDDS) were Capryol™ 90, Tween 80, and Transcutol HP. The impacts of BUD-SMEDDS ingredients (as inputs) on the average globule size (AGS), polydispersity index (PDI), and self-emulsification time (SET) as responses were investigated using the Box–Behnken design methodology. Solid rectal systems were then fabricated using the optimized values of SMEDDS components in Lutrol® bases. The developed systems were evaluated for in vitro characteristics and in vivo efficacy using a rat colitis model.Results: For all responses, the greatest impact was attributed to the oil content of SMEDDS. An optimized BUD-SMEDDS with AGS of 33 ± 2.9 nm, PDI of 0.29 ± 0.03 and SET of 25 ± 2.5 s) was selected for rectal formulations. The developed formulations demonstrated acceptable physical characteristics and mucoadhesive abilities. Differential scanning calorimetric (DSC) analysis revealed the absence of BUD crystallinity in the SMEDDS formulations. The drug release patterns could be regulated by selecting the grade and composition of the incorporated Lutrols. Clinical and histopathological assessments revealed considerable improvements in animals treated with BUD-SMEDDS formulations.Conclusion: Overall findings confirmed the superior capability of solid SMEDDS as BUD carriers to manage distal colitis in tested animals.Keywords: Budesonide, SMEDDS, Ulcerative colitis, Box Behnken design, efficacy

Hany SM Ali,1,2 Nader Namazi,1 Hossein M Elbadawy,3 Abdelaziz AA El-Sayed,4,5 Sameh A Ahmed,6,7 Rawan Bafail,1 Mohannad A Almikhlafi,3 Yaser M Alahmadi8 1Department of Pharmaceutics and Pharmaceutical Industries, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawwarah, Saudi Arabia; 2Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt; 3Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawarah, Saudi Arabia; 4Biology Department, Faculty of Science, Islamic University of Madinah, Madinah, Al-Madinah Al-Munawarah, Saudi Arabia; 5Zoology Department, Faculty of Science, Zagazig University, Zagazig, Al-Sharqiya, Egypt; 6Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawarah, Saudi Arabia; 7Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt; 8Department of Pharmacy Practice, College of Pharmacy, Taibah University, Madinah, Al-Madinah Al-Munawarah, 30001 Saudi ArabiaCorrespondence: Hany SM Ali, Tel +966 50 286 4018, Fax +966 4 847 5027, Email hsali@taibahu.edu.sa; hafandy2000@yahoo.comBackground: Repaglinide (REP) is an antidiabetic drug with limited oral bioavailability attributable to its low solubility and considerable first-pass hepatic breakdown. This study aimed to develop a biodegradable chitosan-based system loaded with REP–solid lipid nanoparticles (REP-SLNs) for controlled release and bioavailability enhancement via transdermal delivery.Methods: REP-SLNs were fabricated by ultrasonic hot-melt emulsification. A Box–Behnken design (BBD) was employed to explore and optimize the impacts of processing variables (lipid content, surfactant concentration, and sonication amplitude) on particle size (PS), and entrapment efficiency (EE). The optimized REP-SLN formulation was then incorporated within a chitosan solution to develop a transdermal delivery system (REP-SLN-TDDS) and evaluated for physicochemical properties, drug release, and ex vivo permeation profiles. Pharmacokinetic and pharmacodynamic characteristics were assessed using experimental rats.Results: The optimized REP-SLNs had a PS of 249± 9.8 nm and EE of 78%± 2.3%. The developed REP-SLN-TDDS demonstrated acceptable characteristics without significant aggregation of REP-SLNs throughout the casting and drying processes. The REP-SLN-TDDS exhibited a biphasic release pattern, where around 36% of the drug load was released during the first 2 h, then the drug release was sustained at around 80% at 24 h. The computed flux across rat skin for the REP-SLN-TDDS was 2.481± 0.22 μg/cm2/h in comparison to 0.696± 0.07 μg/cm2/h for the unprocessed REP, with an enhancement ratio of 3.56. The REP-SLN-TDDS was capable of sustaining greater REP plasma levels over a 24 h period (p< 0.05). The REP-SLN-TDDS also reduced blood glucose levels compared to unprocessed REP and commercial tablets (p< 0.05) in experimental rats.Conclusion: Our REP-SLN-TDDS can be considered an efficient therapeutic option for REP administration.Keywords: repaglinide, chitosan, solid-lipid nanoparticles, Box–Behnken design, transdermal, bioavailability

Hany SM Ali,1,2 Ahmed F Hanafy,1,3 Abdulmalik Alqurshi1 1Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia; 2Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt; 3Research and Development Department, Al Andalous Pharmaceutical Industries, Cairo, Egypt Introduction: Presenting poorly water-soluble drugs as nanoparticles has shown to be an effective technique in enhancing drug dissolution rate, intrinsic solubility, and thus oral bioavailability. Nevertheless, working with nanoparticles introduces many challenges, one of which is their physical instability. Formulating nanoparticles into a solid dosage form may overcome such challenges and thus unlock the potential benefits of nanosizing. Methods: The current work investigates the possibility of developing a novel solid dosage form, with enhanced dissolution rate, whereby nanocrystals (~400 nm) of the class II Biopharmaceutical Classification System drug, glyburide (GBD) were fabricated through combined precipitation and homogenization procedures. Using a novel, but scalable, spraying technique, GBD nanocrystals were loaded onto commonly used tablet fillers, water-soluble lactose monohydrate (LAC), and water insoluble microcrystalline cellulose (MCC). Conventional tableting processes were then used to convert the powders generated into a tablet dosage form. Results: Studies of redispersibility showed considerable preservation of size characteristics of GBD nanocrystals during downstream processing with redispersibility indices of 105 and 118 for GBD–LAC and GBD–MCC, respectively. Characterization by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy showed that the powders generated powders contained nanosized crystals of GBD which adhered to carrier surfaces. Powder flowability was characterized using Hausner ratio (HR) and Carr’s index (CI). GBD–LAC-loaded particles exhibited poor flowability with CI and HR of 37.5% and 1.60, respectively, whilst GBD–MCC particles showed a slightly improved flowability with CI and HR of 26.47% and 1.36, respectively. The novel tablet dosage form met US Pharmacopeia specifications, including drug content, hardness, and friability. Conclusion: Higher dissolution rates were observed from the nanocrystal-based tablets compared to the microsized and commercial drug formulations. Moreover, the novel nanocrystal tablet dosage forms showed enhanced in vivo performance with area under the plasma concentration–time curve in the first 24 hours values 1.97 and 2.24 times greater than that of marketed tablets. Keywords: glyburide, nanocrystals, downstream, tablet, bioavailability, solidification, redispersibility

To investigate 2,017 cases of hantavirus disease in Germany, we compared 38 new patient-derived Puumala virus RNA sequences identified in 2010 with bank vole-derived small segment RNA sequences. The epidemic process was driven by outbreaks of 6 Puumala virus clades comprising strains of human and vole origin. Each clade corresponded to a different outbreak region. [ABSTRACT FROM AUTHOR]

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Background & Aim : Myocardial infarction is a common and dangerous life threatening disease with an impact on quality of life. The present descriptive-analytical study aims to determine quality of life in patients with myocardial infarction referring to Hadjar hospital affiliated to the Shahre-kord University of Medical Sciences. Material & Method : This was a descriptive-analytical study in which 150 patients admitted to cardiac care unit of Hadja hospital within 8 weeks post infarction were selected by non random sampling method. Data were collected through interview, patients’ medical records and patients self report. The tool for collecting data regarding quality of life was SF36 questionnaire. Data were analyzed by descriptive and inferential statistics. Results: Findings showed that the mean value of age was 55.7 ±10.5 and that quality of life in majority of subjects (%53) was fairly favorable. Regarding aspects of quality of life, most patients had fairly favorable general status (physical and psychological health) (%62) and social function (%65). Also, sleep pattern of majority of subjects (%61) was favorable and most of them (62%) had unfavorable physical activity. There was statistically significant correlation between quality of life and variables such as duration of disease (P

This study investigates the fabrication and characterization of n-FeS 2 /p-Si heterojunction photodetectors using chemical bath deposition (CBD) at deposition temperatures ranging from 50 °C to 80 °C. The impact of temperature on the structural, morphological, and optical properties of FeS 2 thin films was evaluated. X-ray diffraction (XRD) revealed polycrystalline cubic FeS 2 with improved crystallinity as the deposition temperature increased. The optical energy gaps of the films ranged from 2.41 eV to 1.6 eV, decreasing with higher temperatures. Scanning electron microscopy (FE-SEM) showed that grain size increased from 30 nm to 180 nm as the temperature rose. Hall effect measurements confirmed the n-type conductivity of the film, with mobility decreasing from 5 to 3.17 cm 2 V -1 s -1 at higher temperatures. The heterojunctions exhibited rectifying behavior, with the best ideality factor of 1.7 observed at 60 °C. The photodetector fabricated at 60 °C showed superior performance, with a responsivity of 0.37 A W -1 at 520 nm and 0.7 A W -1 at 770 nm, an external quantum efficiency of 52%, and a detectivity of 8 × 10 11 Jones at 520 nm, making it the optimal configuration for efficient broadband photodetection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

This study investigated the genotype classification and pathogenicity of infectious bursal disease virus (IBDV) circulating in vaccinated broiler chicken farms in Egypt. A total of 150 samples were collected from 30 vaccinated commercial broiler chicken farms and pooled into 30 working samples. IBDV was tested using reverse transcriptase polymerase chain reaction (RT-PCR) amplification of the hypervariable region of the viral protein 2 (hvVP2) and the VP1 gene 5' extremity. Both RT-PCR fragments were sequenced from six samples, and then the obtained nucleotide sequences were analyzed. The IBDV genotypes were identified using nucleotide sequences. Five sequences of the six strains examined were classified as genotype A3B2 for the highly virulent segments A and B (vv-A/vv-B IBDV). Interestingly, this study identified and classified a novel segment-reassortant strain as the A1B2 genotype. Specifically, it involved the segment reassortment of classical virulent segment A (cv-A) with vv-B producing cv-A/vv-B reassortant IBDV. Subsequently, we compared the pathogenicity of reassortant (cv-A/vv-B) IBDV and vvIBDV strains identified in this study. Both strains developed typical IBD clinical signs, postmortem lesions, histopathology, immunohistochemistry, and lesion scores, which were more severe in vvIBDV than reassortant IBDV. In conclusion, this is the first report of the genotype classification based on both genome segments (hvVP2 and VP1) with pathogenicity of IBDV circulating in vaccinated broiler chicken farms and this pathogenicity is more severe in vvIBDV strain than a novel reassortant IBDV strain., (© 2024. The Author(s).)

Due to the enclosed environment of greenhouse grape production, the supply of CO 2 required for photosynthesis is often insufficient, leading to photosynthetic downregulation and reduced yield. Currently, the optimal CO 2 concentration for grape production in greenhouses is unknown, and the precise control of actual CO 2 levels remains a challenge. This study aims to investigate the effects of different CO 2 concentrations on the photosynthetic characteristics and yield of grapes, to validate the feasibility of a CO 2 gas irrigation system, and to identify the optimal CO 2 concentration for greenhouse grape production. In this study, a CO 2 gas irrigation system combining CO 2 enrichment and gas irrigation techniques was used with a 5-year-old Eurasian grape variety ( Vitis vinifera L.) 'Flame Seedless.' Four CO 2 concentration treatments were applied: 500 ppm (500 ± 30 µmol·mol -1 ), 700 ppm (700 ± 30 µmol·mol -1 ), 850 ppm (850 ± 30 µmol·mol -1 ), and 1,000 ppm (1,000 ± 30 µmol·mol -1 ). As CO 2 concentration increased, chlorophyll a, chlorophyll b, and carotenoids in grape leaves all reached maximum values at 700 ppm and 850 ppm during the same irrigation cycle, while the chlorophyll a/b ratio was lower than at other concentrations. The net photosynthetic rate (Pn) and water use efficiency (WUE) of grape leaves were the highest at 700 ppm. The transpiration rate and stomatal conductance at 700 ppm and 850 ppm were significantly lower than those at other concentrations. The light saturation point and apparent quantum efficiency reached their maximum at 850 ppm, followed by 700 ppm. Additionally, the maximum net photosynthetic rate, carboxylation efficiency, electron transport rate, and activities of SOD, CAT, POD, PPO, and RuBisCO at 700 ppm were significantly higher than at other concentrations, with the highest yield recorded at 14.54 t·hm -2 . However, when the CO 2 concentration reached 1,000 ppm, both photosynthesis and yield declined to varying degrees. Under the experimental conditions, the optimal CO 2 concentration for greenhouse grape production was 700 ppm, with excessive CO 2 levels gradually inhibiting photosynthesis and yield. The results provide a theoretical basis for the future application of CO 2 fertilization and gas irrigation techniques in controlled greenhouse grape production., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou, Mahmoud Ali, Xi, Yao, Zhang, Li, Yu and Zhao.)

The ability to introduce noncanonical amino acids as axial ligands in heme enzymes has provided a powerful experimental tool for studying the structure and reactivity of their Fe IV =O ("ferryl") intermediates. Here, we show that a similar approach can be used to perturb the conserved Fe coordination environment of 2-oxoglutarate (2OG) dependent oxygenases, a versatile class of enzymes that employ highly-reactive ferryl intermediates to mediate challenging C-H functionalizations. Replacement of one of the cis-disposed histidine ligands in the oxygenase VioC with a less electron donating N δ -methyl-histidine (MeHis) preserves both catalytic function and reaction selectivity. Significantly, the key ferryl intermediate responsible for C-H activation can be accumulated in both the wildtype and the modified protein. In contrast to heme enzymes, where metal-oxo reactivity is extremely sensitive to the nature of the proximal ligand, the rates of C-H activation and the observed large kinetic isotope effects are only minimally affected by axial ligand replacement in VioC. This study showcases a powerful tool for modulating the coordination sphere of nonheme iron enzymes that will enhance our understanding of the factors governing their divergent activities., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Tunicates are the sister group to the vertebrates, yet most species have a life cycle split between swimming larva and sedentary adult phases. During metamorphosis, larval neurons are replaced by adult-specific ones. The regulatory mechanisms underlying this replacement remain largely unknown. Using tissue-specific CRISPR/Cas9-mediated mutagenesis in the tunicate Ciona, we show that orthologs of conserved hindbrain and branchiomeric neuron regulatory factors Pax2/5/8 and Phox2 are required to specify the 'neck', a cellular compartment set aside in the larva to give rise to cranial motor neuron-like neurons post-metamorphosis. Using bulk and single-cell RNA-sequencing analyses, we characterize the transcriptome of the neck downstream of Pax2/5/8. We present evidence that neck-derived adult ciliomotor neurons begin to differentiate in the larva and persist through metamorphosis, contrary to the assumption that the adult nervous system is formed after settlement and the death of larval neurons during metamorphosis. Finally, we show that FGF signaling during the larval phase alters the patterning of the neck and its derivatives. Suppression of FGF converts neck cells into larval neurons that fail to survive metamorphosis, whereas prolonged FGF signaling promotes an adult neural stem cell-like fate., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background and Purpose: Erectile dysfunction is a common issue among adult males involving difficulty in maintaining an erection, and it is often treated with fast-acting, low-side-effect drugs like avanafil (AVN), among other phosphodiesterase-5 inhibitors. Hence, developing fast, simple, and sensitive methods to detect AVN is crucial., Experimental Approach: This study conducts an electroanalytical inquiry and provides a new voltammetric method for accurately analyzing AVN utilizing a boron-doped diamond (BDD) electrode without any modifications., Key Results: In the Britton-Robinson buffer (BR, 0.04 mol L -1 , pH 4.0), cyclic voltammetry showed a clearly defined and irreversible anodic peak at around +1.44 V relative to Ag/AgCl. The pH of the solution was shown to have an impact on the voltammetric signals of the oxidation peaks. A good linear response for AVN quantification was achieved using square-wave voltammetry. This was done in a 0.04 mol L-1 BR (pH 4.0) solution at a potential of +1.33 V ( vs. Ag/AgCl). The method exhibited a wide dynamic range of 0.5 to 30.0 μg mL -1 (1.0 to 62 μmol L -1 ) and a low limit of detection of 0.14 μg mL -1 (0.29 μmol L -1 ). The method proposed demonstrated suitability for determining AVN content in pharmaceutical formulations. The accuracy of the approach was demonstrated by comparing the results obtained using the developed method with those achieved using the UV-Vis spectrometry method., Conclusion: Our method simplifies the analytical process by eliminating the need for electrode modification, reducing both time and resource requirements while enhancing overall feasibility., Competing Interests: Conflict of interest: Authors declare that there is no conflict of interest., (Copyright © 2024 by the authors.)

Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC 50 values of 0.12 ± 0.01 and 0.49 ± 0.02 μM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC 50 value of 0.44 ± 0.02 μM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC 50 value of 0.06 ± 0.01 μM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background : Inflammation-mediated insulin resistance in type 2 diabetes mellitus (T2DM) increases complications, necessitating investigation of its mechanism to find new safe therapies. This study investigated the effect of rosavin on the autophagy and the cGAS-STING pathway-related signatures (ZBP1, STING1, DDX58, LC3B, TNF-α) and on their epigenetic modifiers (miR-1976 and lncRNA AC074117.2) that were identified from in silico analysis in T2DM animals. Methods : A T2DM rat model was established by combining a high-fat diet (HFD) and streptozotocin (STZ). After four weeks from T2DM induction, HFD/STZ-induced T2DM rats were subdivided into an untreated group (T2DM group) and three treated groups which received 10, 20, or 30 mg per kg of R. rosea daily for 4 weeks. Results : The study found that rosavin can affect the cGAS-STING pathway-related RNA signatures by decreasing the expressions of ZBP1, STING1, DDX58, and miR-1976 while increasing the lncRNA AC074117.2 level in the liver, kidney, and adipose tissues. Rosavin prevented further weight loss, reduced serum insulin and glucose, improved insulin resistance and the lipid panel, and mitigated liver and kidney damage compared to the untreated T2DM group. The treatment also resulted in reduced inflammation levels and improved autophagy manifested by decreased immunostaining of TNF-α and increased immunostaining of LC3B in the liver and kidneys of the treated T2DM rats. Conclusion : Rosavin has shown potential in attenuating T2DM, inhibiting inflammation in the liver and kidneys, and improving metabolic disturbances in a T2DM animal model. The observed effect was linked to the activation of autophagy and suppression of the cGAS-STING pathway., Competing Interests: All the authors have no conflict of interest to disclose., (This journal is © The Royal Society of Chemistry.)

The enzymatic biosynthesis of fragrance molecules from lignin fragments is an important reaction in biotechnology for the sustainable production of fine chemicals. In this work we investigated the biosynthesis of vanillin from lignostilbene by a nonheme iron dioxygenase using QM/MM and tested several suggested proposals via either an epoxide or dioxetane intermediate. Binding of dioxygen to the active site of the protein results in the formation of an iron(II)-superoxo species with lignostilbene cation radical. The dioxygenase mechanism starts with electrophilic attack of the terminal oxygen atom of the superoxo group on the central C=C bond of lignostilbene, and the second-coordination sphere effects in the substrate binding pocket guide the reaction towards dioxetane formation. The computed mechanism is rationalized with thermochemical cycles and valence bond schemes that explain the electron transfer processes during the reaction mechanism. Particularly, the polarity of the protein and the local electric field and dipole moments enable a facile electron transfer and an exergonic dioxetane formation pathway., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Introduction: Betanin (C₂₄H₂₆N₂O₁₃) is safe to use as food additives approved by the FDA with anti-inflammatory and anticancer effects in many types of cancer cell lines. The current experiment was designed to test the chemotherapeutic effect of the combination of betanin with the standard chemotherapeutic agent, capecitabine, against chemically induced colon cancer in mice. Methods: Bioinformatic approach was designed to get information about the possible mechanisms through which the drugs may control cancer development. Five groups of mice were assigned as, (i) saline, (ii) colon cancer, (iii) betanin, (iv) capecitabine and (v) betanin/capecitabine. Drugs were given orally for a period of six weeks. Colon tissues were separated and used for biological assays and histopathology. Results: In addition, the mRNA expression of TNF-α (4.58-fold), NFκB (5.33-fold), IL-1β (4.99-fold), cyclin D1 (4.07-fold), and IL-6 (3.55-fold) and protein levels showed several folds increases versus the saline group. Tumor histopathology scores in the colon cancer group (including cryptic distortion and hyperplasia) and immunostaining for NFκB (2.94-fold) were high while periodic-acid Schiff staining demonstrated poor mucin content (33% of the saline group). These pathologic manifestations were reduced remarkably in betanin/capecitabine group. Conclusion: Collectively, our findings demonstrated the usefulness of betanin/capecitabine combination in targeting colon cancer and highlighted that betanin is a promising adjuvant therapy to capecitabine in treating colon cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ahmed, Zaitone, Abdelmaogood, Atef, Soliman, Badawy, Ali, Zaid, Mokhtar, Elabbasy, Kandil, Yosef and Mahran.)

In the aquaculture industry, silica nanoparticles (SiNPs) have great significance, mainly for confronting diseases. Therefore, the present study aims to assess the antibacterial efficiency of SiNPs as a versatile trial against Aeromonas veronii infection in African catfish (Clarias gariepinus). Further, we investigated the influence of SiNPs in palliating the immune-antioxidant stress biochemical, ethological, and histopathological alterations induced by A. veronii. The experiment was conducted for 10 days, and about 120 fish were distributed into four groups at random, with 30 fish each. The first group is a control that was neither exposed to infection nor SiNPs. The second group (SiNPs) was vulnerable to SiNPs at a concentration of 20 mg/L in water. The third group was experimentally infected with A. veronii at a concentration of 1.5 × 10 7 CFU/mL. The fourth group (A. veronii + SiNPs) was exposed to SiNPs and infected with A. veronii. Results outlined that A. veronii infection induced behavioral alterations and suppression of immune-antioxidant responses that appeared as a clear decline in protein profile indices, complement 3, lysozyme activity, glutathione peroxidase, and total antioxidant capacity. The kidney and liver function biomarkers (creatinine, urea, alkaline phosphatase, and alanine aminotransferase) and lipid peroxide (malondialdehyde) were substantially increased in the A. veronii group, with marked histopathological changes and immunohistochemical alterations in these tissues. Interestingly, the exposure to SiNPs resulted in a clear improvement in all measured biomarkers and a noticeable regeneration of the histopathological changes. Overall, it will establish that SiNPs are a new, successful tool for opposing immunological, antioxidant, physiological, and histopathological alterations induced by A. veronii infection., (© 2023. The Author(s).)

Many enzymes in nature utilize a free arginine (L-Arg) amino acid to initiate the biosynthesis of natural products. Examples include nitric oxide synthases, which generate NO from L-Arg for blood pressure control, and various arginine hydroxylases involved in antibiotic biosynthesis. Among the groups of arginine hydroxylases, several enzymes utilize a nonheme iron(II) active site and let L-Arg react with dioxygen and α -ketoglutarate to perform either C 3 -hydroxylation, C 4 -hydroxylation, C 5 -hydroxylation, or C 4 -C 5 -desaturation. How these seemingly similar enzymes can react with high specificity and selectivity to form different products remains unknown. Over the past few years, our groups have investigated the mechanisms of L-Arg-activating nonheme iron dioxygenases, including the viomycin biosynthesis enzyme VioC, the naphthyridinomycin biosynthesis enzyme NapI, and the streptothricin biosynthesis enzyme OrfP, using computational approaches and applied molecular dynamics, quantum mechanics on cluster models, and quantum mechanics/molecular mechanics (QM/MM) approaches. These studies not only highlight the differences in substrate and oxidant binding and positioning but also emphasize on electronic and electrostatic differences in the substrate-binding pockets of the enzymes. In particular, due to charge differences in the active site structures, there are changes in the local electric field and electric dipole moment orientations that either strengthen or weaken specific substrate C-H bonds. The local field effects, therefore, influence and guide reaction selectivity and specificity and give the enzymes their unique reactivity patterns. Computational work using either QM/MM or density functional theory (DFT) on cluster models can provide valuable insights into catalytic reaction mechanisms and produce accurate and reliable data that can be used to engineer proteins and synthetic catalysts to perform novel reaction pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declare that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ali and de Visser.)

Probiotics and their bacteriocins have increasingly attracted interest for their use as safe food preservatives. This study aimed to produce soft white cheese fortified with Lacticaseibacillus MG847589 ( Lb. paracasei MG847589) and/or its bacteriocin; cheese with Lacticaseibacillus (CP), cheese with bacteriocin (CB), and cheese with both Lacticaseibacillus and bacteriocin (CPB) were compared to control cheese (CS) to evaluate their biopreservative and anti-mycotoxigenic potentials for prolonged shelf life and safe food applications. The effects of these fortifications on physiochemical, microbial, texture, microstructure, and sensory properties were studied. Fortification with Lacticaseibacillus (CP) increased acidity (0.61%) and microbial counts, which may make the microstructure porous, while CPB showed intact microstructure. The CPB showed the highest hardness value (3988.03 g), while the lowest was observed with CB (2525.73 g). Consequently, the sensory assessment reflected the panelists' preference for CPB, which gained higher scores than the control (CS). Fortification with Lb. paracasei MG847589 and bacteriocin (CPB) showed inhibition effects against S. aureus from 6.52 log 10 CFU/g at time zero to 2.10 log 10 CFU/g at the end of storage, A. parasiticus (from 5.06 to 3.03 log 10 CFU/g), and P. chrysogenum counts (from 5.11 to 2.86 log 10 CFU/g). Additionally, CPB showed an anti-mycotoxigenic effect against aflatoxins AFB 1 and AFM 1 , causing them to be decreased (69.63 ± 0.44% and 71.38 ± 0.75%, respectively). These potentials can extend shelf life and pave the way for more suggested food applications of safe food production by fortification with both Lb. paracasei MG847589 and its bacteriocin as biopreservatives and anti-mycotoxigenic.

Introduction: Medical simulation has become an essential teaching method for all health professionals. It not only allows to acquire technical and non-technical knowledge, but also helps the maintenance of acquired knowledge in the medium and long term. Ascites puncture is part of the basic technical procedures learned by medical students during their internship., Objectives: To evaluate the role of simulation-based learning of ascites puncture on the improvement of theoretical knowledge and maintenance of skills at 3 months., Methods: We conducted an audit type study with two cycles of data collection at the simulation center at the Faculty of Medicine of Sousse between November 2020 and June 2021. We included learners in their third year of medical studies who had a hospital internship in the gastroenterology department at Sahloul Hospital in Sousse. All learners attended the initial simulation session on ascites fluid puncture. Thereafter, they were free to accept or refuse participation in the evaluation session that was scheduled after 3 months, depending on their availability., Results: Forty learners participated in the procedural simulation of the ascites fluid puncture technique. Thirty-four (85%) were female and six (5%) were male. In our study, we showed that following procedural simulation training of ascites puncture, there was a significant improvement in the theoretical knowledge of the learners (p < 0.000). Objective assessment of technical skills after 3 months showed the benefit of performance maintenance (p < 0.000)., Conclusion: Our study confirmed the benefit of simulation-based learning on the improvement of theoretical knowledge and the maintenance of technical performance in the medium term., (© 2024. The Author(s).)

Artificial metalloenzymes (ArMs) have emerged as a promising avenue in the field of biocatalysis, offering new reactivity. However, their design remains challenging due to the limited understanding of their protein dynamics and how the introduced cofactors alter the protein scaffold structure. Here we present the structures and catalytic activity of novel copper ArMs capable of ( R )- or ( S )-stereoselective control, utilizing a steroid carrier protein (SCP) scaffold. To incorporate 2,2'-bipyridine (Bpy) into SCP, two distinct strategies were employed: either Bpy was introduced as an unnatural amino acid (2,2'-bipyridin-5-yl)alanine (BpyAla) using amber stop codon expression or via bioconjugation of bromomethyl-Bpy to cysteine residues. The resulting ArMs proved to be effective at catalysing an enantioselective Friedel-Crafts reaction with SCP&#95;Q111BpyAla achieving the best selectivity with an enantioselectivity of 72% ee ( S ). Interestingly, despite using the same protein scaffold, different attachment strategies for Bpy at the same residue (Q111) led to a switch in the enantiopreference of the ArM. X-ray crystal structures of SCP&#95;Q111CBpy and SCP&#95;Q111BpyAla ArMs with bound Cu(ii) ions unveiled crucial differences in the orientation of the catalytic centre. Combining structural information, alanine scanning studies, and computational analysis shed light on the distinct active sites of the ArMs, clarifying that these active sites stabilise the nucleophilic substrate on different sides of the electrophile leading to the observed switch in enantioselectivity. This work underscores the importance of integrating structural studies with catalytic screening to unravel the intricacies of ArM behaviour and facilitate their development for targeted applications in biocatalysis., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Non-homologous end joining, an important DNA-double-stranded break repair pathway, plays a prominent role in conferring resistance to radiotherapeutic agents, resulting in cancer progression and relapse., Purpose: The molecular players involved in the radio-sensitizing effects of piperine and many other phytocompounds remain evasive to a great extent. The study is designed to assess if piperine, a plant alkaloid can alter the radioresistance by modulating the expression of non-homologous end-joining machinery., Methods and Materials: Estrogen receptor-positive/negative, breast cancer cells were cultured to understand the synergetic effects of piperine with radiotherapy. Cisplatin and Bazedoxifene were used as positive controls. Cells were exposed to γ- radiation using Low Dose gamma Irradiator-2000. The piperine effect on Estrogen receptor modulation, DNA-Damage, DNA-Damage-Response, and apoptosis was done by western blotting, immunofluorescence, yeast-based-estrogen-receptor-LacZ-reporter assay, and nuclear translocation analysis. Micronuclei assay was done for DNA damage and genotoxicity, and DSBs were quantified by γH2AX-foci-staining using confocal microscopy. Flow cytometry analysis was done to determine the cell cycle, mitochondrial membrane depolarization, and Reactive oxygen species generation. Pharmacophore analysis and protein-ligand interaction studies were done using Schrodinger software. Synergy was computed by compusyn-statistical analysis. Standard errors/deviation/significance were computed with GraphPad prism., Results: Using piperine, we propose a new strategy for overcoming acquired radioresistance through estrogen receptor-mediated modulation of the NHEJ pathway. This is the first comprehensive study elucidating the mechanism of radio sensitizing potential of piperine. Piperine enhanced the radiation-induced cell death and enhanced the expression and activation of Estrogen receptor β, while Estrogen receptor α expression and activation were reduced. In addition, piperine shares common pharmacophore features with most of the known estrogen agonists and antagonists. It altered the estrogen receptor α/β ratio and the expression of estrogen-responsive proteins of DDR and NHEJ pathway. Enhanced expression of DDR proteins, ATM, p53, and P-p53 with low DNA-PK repair complex (comprising of DNA-PKcs/Ku70/Ku80), resulted in the accumulation of radiation-induced DNA double-stranded breaks (as evidenced by MNi and γH2AX-foci) culminating in cell cycle arrest and mitochondrial-pathway of apoptosis., Conclusion: In conclusion, our study for the first time reported that piperine sensitizes breast cancer cells to radiation by accumulating DNA breaks, through altering the expression of DNA-PK Complex, and DDR proteins, via selective estrogen receptor modulation, offering a novel strategy for combating radioresistance., Competing Interests: Declaration of Competing Interest Authors hereby declare that they don't have any conflicting interests to declare, (Copyright © 2023 Elsevier GmbH. All rights reserved.)

As the importance of reliable multimedia content increases in today's society, image forensics is a growing field of research. The act of copying and pasting specific parts of an image, known as copy-move forgery, may be utilized for illegal or unethical purposes. Just as with other vision-related technologies, the accuracy of forensic analysis depends on having an appropriate image representation. Most existing feature extraction techniques do not accurately reflect the underlying image content leading to reduced performance. In this article, to detect the copy-move forgery attack, the Generic Radial Harmonic Fourier Moment (GRHFM) is proposed for reliable and distinctive image representation. The algorithm has the ability to effectively manipulate the distribution of zeros to emphasize certain image regions. Additionally, the relationships between complex exponentials and trigonometric functions are exploited to efficiently compute and easily implement the transform kernels. The efficacy of the algorithm is illustrated through experiments on dense-domain-based matching patterns. Experimental results on five benchmarking databases prove the effectiveness of the proposed approach compared with the state-of-the-art methods. According to the average scores, the proposed method demonstrates superior accuracy in overall localization performance. The F1 score, precision, and recall percentage values obtained are 92.5, 95.44, and 91.96, respectively. Robustness experiments on more challenging attacks are also conducted on FAU dataset. Results show that the proposed framework satisfies invariance to the various image variations, and thus an enhanced robustness compared to the previous methods. Moreover, the advantage of reasonable computational cost implies its potential use in real-world forensic applications., (© 2023 American Academy of Forensic Sciences.)

The coronavirus, a subfamily of the coronavirinae family, is an RNA virus with over 40 variations that can infect humans, non-human mammals and birds. There are seven types of human coronaviruses, including SARS-CoV-2, is responsible for the recent COVID-19 pandemic. The current study is focused on the identification of drug molecules for the treatment of COVID-19 by targeting human proteases like transmembrane serine protease 2 (TMPRSS2), furin, cathepsin B, and a nuclear receptor named farnesoid X receptor (FXR). TMPRSS2 and furin help in cleaving the spike protein of the SARS-CoV-2 virus, while cathepsin B plays a critical role in the entry and pathogenesis. FXR, on the other hand, regulates the expression of ACE2, and its inhibition can reduce SARS-CoV-2 infection. By inhibiting these four protein targets with non-toxic inhibitors, the entry of the infectious agent into host cells and its pathogenesis can be obstructed. We have used the BioSolveIT suite for pharmacophore-based computational drug designing. A total of 1611 ligands from the ligand library were docked with the target proteins to obtain potent inhibitors on the basis of pharmacophore. Following the ADMET analysis and protein ligand interactions, potent and druggable inhibitors of the target proteins were obtained. Additionally, toxic substructures and the less toxic route of administration of the most potent inhibitors in rodents were also determined computationally. Compounds namely N-(diaminomethylene)-2-((3-((1R,3R)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclopentyl)propyl)amino)-2-oxoethan-1-aminium (26), (1R,3R)-3-(((2-ammonioethyl)ammonio)methyl)-1-((4-propyl-1H-imidazol-2-yl)methyl)piperidin-1-ium (29) and (1R,3R)-3-(((2-ammonioethyl)ammonio)methyl)-1-((1-propyl-1H-pyrazol-4-yl)methyl)piperidin-1-ium (30) were found as the potent inhibitors of TMPRSS2, whereas, 1-(1-(1-(1H-tetrazol-1-yl)cyclopropane-1‑carbonyl)piperidin-4-yl)azepan-2-one (6), (2R)-4-methyl-1-oxo-1-((7R,11S)-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,11-methanopyrido[1,2-a]azocin-9-yl)pentan-2-aminium (12), 4-((1-(3-(3,5-dimethylisoxazol-4-yl)propanoyl)piperidin-4-yl)methyl)morpholin-4-ium (13), 1-(4,6-dimethylpyrimidin-2-yl)-N-(3-oxocyclohex-1-en-1-yl)piperidine-4-carboxamide (14), 1-(4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(3,5-dimethylisoxazol-4-yl)propan-1-one (25) and N,N-dimethyl-4-oxo-4-((1S,5R)-8-oxo-5,6-dihydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-3(2H,4H,8H)-yl)butanamide (31) inhibited the FXR preferentially. In case of cathepsin B, N-((5-benzoylthiophen-2-yl)methyl)-2-hydrazineyl-2-oxoacetamide (2) and N-([2,2'-bifuran]-5-ylmethyl)-2-hydrazineyl-2-oxoacetamide (7) were identified as the most druggable inhibitors whereas 1-amino-2,7-diethyl-3,8-dioxo-6-(p-tolyl)-2,3,7,8-tetrahydro-2,7-naphthyridine-4‑carbonitrile (5) and (R)-6-amino-2-(2,3-dihydroxypropyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (20) were active against furin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Yellow fever is a flavivirus having plus-sensed RNA which encodes a single polyprotein. Host proteases cut this polyprotein into seven nonstructural proteins including a vital NS3 protein. The present study aims to identify the most effective inhibitor against the helicase (NS3) using different advanced ligand and structure-based computational studies. A set of 300 ligands was selected against helicase by chemical structural similarity model, which are similar to S -adenosyl-l-cysteine using infiniSee. This tool screens billions of compounds through a similarity search from in-built chemical spaces (CHEMriya, Galaxi, KnowledgeSpace and REALSpace). The pharmacophore was designed from ligands in the library that showed same features. According to the sequence of ligands, six compounds ( 29 , 87 , 99 , 116 , 148 , and 208 ) were taken for pharmacophore designing against helicase protein. Subsequently, compounds from the library which showed the best pharmacophore shared-features were docked using FlexX functionality of SeeSAR and their optibrium properties were analyzed. Afterward, their ADME was improved by replacing the unfavorable fragments, which resulted in the generation of new compounds. The selected best compounds ( 301 , 302 , 303 and 304 ) were docked using SeeSAR and their pharmacokinetics and toxicological properties were evaluated using SwissADME. The optimal inhibitor for yellow fever helicase was 2-amino- N -(4-(dimethylamino)thiazol-2-yl)-4-methyloxazole-5-carboxamide ( 302 ), which exhibits promising potential for drug development.Communicated by Ramaswamy H. Sarma.

The identification of effective and druggable cholinesterase inhibitors to treat progressive neurodegenerative Alzheimer's disorder remains a continuous drug discovery hunt. In this perspective, the present study investigates the design and discovery of pyrimidine-morpholine hybrids (5a-l) as potent cholinesterase inhibitors. Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction was employed to introduce the structural diversity on the pyrimidine heterocyclic core. A range of commercially available boronic acids was successfully coupled showing a high functional group tolerance. In vitro cholinesterase inhibitory potential using Ellman's method revealed significantly strong potency. Compound 5h bearing a meta-tolyl substituent at 2-position of pyrimidine ring emerged as a lead candidate against AChE with an inhibitory potency of 0.43 ± 0.42 µM, ∼38-fold stronger value than neostigmine (IC 50  = 16.3 ± 1.12 µM). Compound 5h also showed the lead inhibition against BuChE with an IC 50 value of 2.5 ± 0.04 µM. The kinetics analysis of 5h revealed the non-competitive mode of inhibition against AChE whereas computational modelling results of potent leads depicted diverse contacts with the binding site amino acid residues. Molecular dynamics simulations revealed the stability of biomolecular system, while, ADME analysis demonstrated druglikeness behaviour of potent compounds. Overall, the investigated pyrimidine-morpholine scaffold presented a remarkable potential to be developed as efficacious anti-Alzheimer's drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Severe COVID-19 is associated with a dysregulated immune response that usually leads to cytokine release syndrome. This study aimed to compare the use of extracorporeal blood purification therapy (Oxiris ® ) versus standard continuous renal replacement therapy (CRRT) in critically-ill patients with severe COVID-19., Methods: This was a national, multicenter, retrospective study of patients with COVID-19 admitted to the intensive care unit (ICU) between March and October 2020 who required CRRT. Patients were categorized into two groups: Oxiris ® CRRT and standard CRRT. The primary outcome was the number of patients alive and ventilator-free at 30-days post-CRRT treatment. Key secondary endpoints included change in inflammatory markers, Sequential Organ Failure Assessment (SOFA) scores, and PaO 2 /FiO 2 ratio at 24- and 72-h post Oxiris ® initiation., Results: Thirty-five patients received Oxiris ® CRRT and 23 patients received standard CRRT. The primary outcome was 31.4% in the Oxiris ® group versus 4.3% in the standard CRRT group (adjusted odds ratio 5.97, 95% confidence interval [CI], 0.64-55.6; p  = 0.117). In the Oxiris ® group, interleukin-6 (IL-6) concentrations significantly decreased at 24 and 72-h ( p  = 0.033) and PaO 2 /FiO 2 ratio significantly increased at 24 and 72 h after Oxiris ® initiation ( p  = 0.001). There was no significant change in SOFA scores at 24- and 72-h after Oxiris ® initiation., Conclusion: The number of patients alive and ventilator-free at 30-days was higher in the Oxiris ® group than that in the standard CRRT group; however, the difference did not reach statistical significance after adjusting for the baseline severity of illness. There was a significant reduction in IL-6 and significant improvement in PaO 2 /FiO 2 ratio after Oxiris ® CRRT initiation., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Statement of Problem: Custom-made angled LOCATOR abutments have been used to compensate for the angulation of implants placed to support removable prostheses; however, their retention forces and the impact of mastication loading on retention have yet to be well addressed., Purpose: The purpose of this in vitro study was to evaluate the retention force of custom-made LOCATOR abutments for implants placed at 0-, 15-, and 30-degree angulations with prefabricated abutments and to investigate the effect of mastication load on retention., Material and Methods: Implant analogs were placed at the first molars of 40 maxillary typodonts, and 40 LOCATOR abutments were fabricated. Twenty implant analogs were placed at 0 degrees, 10 of which received prefabricated LOCATOR abutments and 10 of which received custom abutments. The remaining 20 implant analogs were placed at 15- and 30-degree angulations (n=10), and custom LOCATOR abutments were fabricated on them. A denture analog was digitally designed and manufactured from polymethyl methacrylate (PMMA) billets. Metal housings were then picked up using PMMA. The specimens were subjected to 2 rounds of 120 000 cycles of mastication loading. Retention force was assessed before and after each round of mastication loading using a universal testing machine. The wear of nylon inserts before and after mastication loading was accessed with a digital stereomicroscope. A 2-way ANOVA followed by the Tukey HSD test was used to determine the impacts of LOCATOR abutment type and times of mastication loading on the retention forces of the denture base (α=.05)., Results: No significant difference in retention forces was found between prefabricated LOCATOR and custom abutments (placed at 0-, 15-, and 30-degree angulations) regardless of mastication loading (P>.05). The retentive force values of all groups increased significantly after the first round of mastication loading and decreased significantly to the initial level after the second round of mastication loading (P<.05)., Conclusions: Mastication loading impacted the retention force of both prefabricated and custom LOCATOR abutments; however, no significant difference in retention forces was found among various types of abutments., (Copyright © 2023 Editorial Council for The Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

The energy-entropy multiscale cell correlation (EE-MCC) method is used to calculate toluene-water log  P values of 16 drug molecules in the SAMPL9 physical properties challenge. EE-MCC calculates the free energy, energy and entropy from molecular dynamics (MD) simulations of the water and toluene solutions. Specifically, MCC evaluates entropy by partitioning the system into cells of correlated atoms at multiple length scales and further partitioning the local coordinates into energy wells, yielding vibrational and topographical terms from the energy-well sizes and probabilities. The log  P values calculated by EE-MCC using three 200 ns MD simulations have a mean average error of 0.82 and standard error of the mean of 0.97 versus experiment, which is comparable with the best methods entered in SAMPL9. The main contribution to log  P is from energy. Less polar drugs have more favourable energies of transfer. The entropy of transfer consists of increased solute vibrational and conformational terms in toluene due to weaker interactions, fewer solute positions in the larger-molecule solvent, reduced water vibrational entropy, negligible change in toluene vibrational entropy, and gains in solvent orientational entropy. The solvent entropy contributions here may be slightly underestimated because software limitations and statistical fluctuations meant that only the first shell could be included while averaged over the whole solution. Nonetheless, such issues will be addressed in future software to offer a general method to calculate entropy directly from MD simulation and to provide molecular understanding or guide system design.

Parkinson's disease (PD) is a gradual deterioration of dopaminergic neurons, leading to motor impairments. Social isolation (SI), a recognized stressor, has recently gained attention as a potential influencing factor in the progress of neurodegenerative illnesses. We aimed to investigate the intricate relationship between SI and PD progression, both independently and in the presence of manganese chloride (MnCl 2 ), while evaluating the punicalagin (PUN) therapeutic effects, a natural compound established for its cytoprotective, anti-inflammatory, and anti-apoptotic activities. In this five-week experiment, seven groups of male albino rats were organized: G1 (normal control), G2 (SI), G3 (MnCl 2 ), G4 (SI + MnCl 2 ), G5 (SI + PUN), G6 (MnCl 2 + PUN), and G7 (SI + PUN + MnCl 2 ). The results revealed significant changes in behavior, biochemistry, and histopathology in rats exposed to SI and/or MnCl 2 , with the most pronounced effects detected in the SI rats concurrently exposed to MnCl 2 . These effects were associated with augmented oxidative stress biomarkers and reduced antioxidant activity of the Nrf2/HO-1 pathway. Additionally, inflammatory pathways (HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1 and JAK-2/STAT-3) were upregulated, while dysregulation of signaling pathways (PI3K/AKT/GSK-3β/CREB), sustained endoplasmic reticulum stress by activation PERK/CHOP/Bcl-2, and impaired autophagy (AMPK/SIRT-1/Beclin-1 axis) were observed. Apoptosis induction and a decrease in monoamine levels were also noted. Remarkably, treatment with PUN effectively alleviated behaviour, histopathological changes, and biochemical alterations induced by SI and/or MnCl 2 . These findings emphasize the role of SI in PD progress and propose PUN as a potential therapeutic intervention to mitigate PD. PUN's mechanisms of action involve modulation of pathways such as HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1, JAK-2/STAT-3, PI3K/AKT/GSK-3β/CREB, AMPK/SIRT-1, Nrf2/HO-1, and PERK/CHOP/Bcl-2.

Propolis is a naturally occurring substance with beneficial properties; bees produce it from various plant sources, and it is an anti-inflammatory and therapeutic resinous substance. This study aimed to enhance the biological features of propolis extract by loading it onto active film. Firstly, extraction was performed using three solvent systems, and their total phenolic, flavonoid, and antioxidant activity was measured. Propolis ethanol extract (EEP) was evaluated for phenolic fraction content and then chosen to prepare a chitosan-loaded emulsion with several concentrations. The antibacterial, anti-mycotic, and anti-mycotoxigenic properties of the extract and nanoemulsion were assessed. PPE's cytotoxicity and nanoemulsion were evaluated using brine shrimp and cell line assays. Results indicate higher phenolic (322.57 ± 4.28 mg GAE/g DW), flavonoid (257.64 ± 5.27 mg QE/g DW), and antioxidant activity of the EEP. The phenolic fraction is distinguished by 18 phenolic acids with high p -hydroxybenzoic content (171.75 ± 1.64 µg/g) and 12 flavonoid compounds with high pinocembrin and quercetin content (695.91 ± 1.76 and 532.35 ± 1.88 µg/g, respectively). Phenolic acid derivatives (3,4-Dihydroxybenzaldehyde, 3,4-Dihydroxyphenol acetate, and di-methoxy cinnamic) are also found. Concentrations of 50, 100, 150, and 200 ng EEP loaded on chitosan nanoemulsion reflect significant antibacterial activity against pathogenic bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA) and toxigenic fungi, particularly Fusarium . Among the four EEP-loaded concentrations, the nanoemulsion with 150 ng showed outstanding features. Using a simulated medium, 150 and 200 ng of EEP-loaded chitosan nanoemulsion concentrations can stop zearalenone production in Fusarium media with complete fungi inhibition. Also, it reduced aflatoxins production in Aspergillus media, with fungal inhibition (up to 47.18%). These results recommended the EEP-chitosan application for pharmaceutics and medical use as a comprehensive wound healing agent.

The milk's natural flora, or the starter, can preserve cheesemaking and allow for microbial competition. This investigation aimed to improve cheese safety and assess its characteristics using probiotic cell pellets (LCP) or cell-free extracts (CFS). Cheese samples were collected from different areas to investigate the current contamination situation. Six CFSs of probiotics were assessed as antifungal against toxigenic fungi using liquid and solid media and their aflatoxin reduction impact. The most effective CFS was chosen for cheese coating in nanoemulsion. Coated cheese with CFS, LCP, and LCP-CFS was assessed against control for changes in chemical composition, ripening indications, rheological properties, and microbiology. Results showed significant contamination levels in the collected samples, and toxic fungi were present. Lactobacillus rhamnosus CFS has aflatoxins reducibility in liquid media. During cheese ripening, uncoated cheese showed higher fat, protein, salt content, soluble nitrogen, total volatile fatty acids, tyrosine, and tryptophan contents than coated samples, except for LCP-coating treatment. Cheese rheology indicated that coating treatments had the lowest hardness, cohesiveness, gumminess, chewiness, and springiness compared to uncoated cheese. Uncoated cheese had the highest yeast and mold counts compared to the treated ones. The LCP-CFS-coated cheese showed no Aspergillus cells for up to 40 days. Uncoated Ras cheese recorded slightly lower flavor, body, texture, and appearance scores than coated cheeses. In conclusion, coating cheese with L. rhamnosus nanoemulsion has antifungal and antiaflatoxigenic properties, even for LCP, CFS, and CFS-LCP, which could extend cheese shelf life.

Riemerella anatipestifer (RA) is a common disease causing economic losses to duck farms worldwide. Novel supplements are crucially needed to control this bacterium, enhance poultry performance, and produce synergistic effects with vaccines in stimulating the immune system. This study investigated the effect of nano-selenium (Nano-Se) on the vaccinated (VAC) and challenged (Ch) Pekin ducklings (Anas platyrhynchos) with RA. Five experimental groups (G1-G5) were included in this study: G1 was the control group, G2 was the RA-challenged group, G3 was the Nano-Se+Ch group, G4 was the VAC+Ch group, and G5 was the Nano-Se+VAC+Ch group. The Nano-Se (0.3 mg/kg diet) was supplemented for 5 weeks post-vaccination (PV). The ducklings were vaccinated subcutaneously with the RA vaccine at 7 days of age and challenged with RA at the 3rd week PV. Blood, pharyngeal swabs and tissue samples were collected at the 3rd week PV and at different times post-challenge (PC). The growth performance (weight gain and feed conversion ratio), clinical signs, gross lesions, mortality, bacterial shedding, haematological, immunological, and biochemical parameters, cytokines production, and histopathological lesion scores showed significant differences (P < 0.05) between the challenged (G2) group and the supplemented (G3 & G5) groups. G5 showed the highest (P < 0.05) growth performance, phagocytic activity, IgM and IgG, splenic interleukin-2 (IL-2), IL-10, and interferon-gamma (IFN-γ) gene expressions, and the lowest mortality, bacterial shedding, hepatic and renal damage, heterophil/lymphocyte ratio and lesion scores compared to the other groups. In conclusion, the supplementation of nano-selenium for five weeks in the diet can improve the growth performance, immune status, and cytokines production in ducklings vaccinated and challenged with RA., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The current study aimed to test the neuroprotective action of topiramate in mouse peripheral diabetic neuropathy (DN) and explored some mechanisms underlying this action. Mice were assigned as vehicle group, DN group, DN + topiramate 10-mg/kg and DN + topiramate 30-mg/kg. Mice were tested for allodynia and hyperalgesia and then spinal cord and sciatic nerves specimens were examined microscopically and neurofilament heavy chain (NEFH) immunostaining was performed. Results indicated that DN mice had lower the hotplate latency time (0.46-fold of latency to licking) and lower von-Frey test pain threshold (0.6-fold of filament size) while treatment with topiramate increased these values significantly. Sciatic nerves from DN control mice showed axonal degeneration while spinal cords showed elevated GFAP (5.6-fold) and inflammatory cytokines (∼3- to 4-fold) but lower plasticity as indicated by GAP-43 (0.25-fold). Topiramate produced neuroprotection and suppressed spinal cord GFAP/inflammation but enhanced GAP-43. This study reinforces topiramate as neuroprotection and explained some mechanisms included in alleviating neuropathy.

Stroke ranks as the world's second most prevalent cause of mortality, and it represents a major public health concern with profound economic and social implications. In the present study, we elucidated the neuroprotective role of quercetin on NLRP3-associated pyroptosis, Nrf2-coupled anti-inflammatory, and mTOR-dependent downstream pathways. Male Sprague Dawley rats were subjected to 72 h of transient middle cerebral artery ischemia, followed by the administration of 10 mg/kg of quercetin. Our findings demonstrated that MCAO induced elevated ROS which were coupled to inflammasome-mediated pyroptosis and altered mTOR-related signaling proteins. We performed ELISA, immunohistochemistry, and Western blotting to unveil the underlying role of the Nrf2/HO-1 and PDK/AKT/mTOR pathways in the ischemic cortex and striatum. Our results showed that quercetin post-treatment activated the Nrf2/HO-1 cascade, reversed pyroptosis, and modulated the autophagy-related pathway PDK/AKT/mTOR/P70S6/P6/eIF4E/4EBP1. Further, quercetin enhances the sequestering effect of 14-3-3 and reversed the decrease in interaction between p-Bad and 14-3-3 and p-FKHR and 14-3-3. Our findings showed that quercetin exerts its protective benefits and rescues neuronal damage by several mechanisms, and it might be a viable neuroprotective drug for ischemic stroke therapy.

Energetic heterocycles, including pyridines, triazoles, and tetrazoles, exhibit greater density, heats of formation, and oxygen balance compared to their carbocyclic counterparts, making them a promising approach for synthesizing novel bis-tetrazole acetamides. Synthesized compounds A-F, some of which feature a chlorine atom attached to the phenyl ring, serve as valuable synthons for aryl coupling reactions. Analysis via 1 H-NMR and 13 C-NMR spectroscopy, as well as density functional considerations through B3LYP functional correlation with 6-311 +  + G(d) and 6-31G(d) basis set, revealed the observed LUMO/HOMO energies and charge transfer within the molecule. Additionally, the dipole moment, chemical hardness, softness, ionization potential, local reactivity potential via Fukui indices and thermodynamic properties (entropy, enthalpy, and Gibbs free energy) of the molecule were calculated through density functional theory studies. In addition, Molecular Docking studies were conducted to investigate the anti-cancer potential of synthesized heterocyclic compounds against caspase 3, NF-KAPPA-B and P53 protein. Molecular docking analysis demonstrated a potent interaction between 2,2'-(5,5'-(1,4-phenylene)bis(1H-tetrazole-5,1-diyl))bis-N-(2,4-dinitrophenyl) acetamides (6d) and TP53 and NF-KAPPA-B with binding energies of - 11.8 kJ/mol and - 10.9 kJ/mol for TP53 and NF-KAPPA-B, respectively. Similarly, 2,2'-(5,5'-(1,4-phenylene)bis(1H-tetrazole-5,1-diyl))bis-N-(2-chlorophenyl) acetamides (6f) exhibited a strong interaction with caspase-3 with binding energy of -10.0 kJ/mol, indicating their potential as therapeutic agents against these proteins. Furthermore, the findings of current study was further strengthen by 100 ns molecular dynamics (MD) simulations. Finally, theoretical studies of oxygen balance and nitrogen percentage suggest that these molecules can be utilized as energetic materials., (© 2023. Springer Nature Switzerland AG.)

Medicinal plant extracts are a promising source of bioactive minor contents. The present study aimed to evaluate the distinguished volatile content of Algerian Cymbopogon citratus (DC.) Stapf before and after the microfluidization process and their related antimicrobial and anti-mycotoxigenic impacts and changes. The GC-MS apparatus was utilized for a comparative examination of Algerian lemongrass essential oil (LGEO) with its microfluidization nanoemulsion (MF-LGEO) volatile content. The MF-LGEO was characterized using Zetasizer and an electron microscope. Cytotoxicity, antibacterial, and antifungal activities were determined for the LGEO and MF-LGEO. The result reflected changes in the content of volatiles for the MF-LGEO. The microfluidizing process enhanced the presence of compounds known for their exceptional antifungal and antibacterial properties in MF-LGEO, namely, neral, geranial, and carvacrol. However, certain terpenes, such as camphor and citronellal, were absent, while decanal, not found in the raw LGEO, was detected. The droplet diameter was 20.76 ± 0.36 nm, and the polydispersity index (PDI) was 0.179 ± 0.03. In cytotoxicity studies, LGEO showed higher activity against the HepG2 cell line than MF-LGEO. Antibacterial LGEO activity against Gram-positive bacteria recorded an inhibitory zone from 41.82 ± 2.84 mm to 58.74 ± 2.64 mm, while the zone ranged from 12.71 ± 1.38 mm to 16.54 ± 1.42 mm for Gram-negative bacteria. Antibacterial activity was enhanced to be up to 71.43 ± 2.54 nm and 31.54 ± 1.01 nm for MF-LGEO impact against Gram-positive and Gram-negative pathogens. The antifungal effect was considerable, particularly against Fusarium fungi. It reached 17.56 ± 1.01 mm and 13.04 ± 1.37 mm for LGEO and MF-LGEO application of a well-diffusion assay, respectively. The MF-LGEO was more promising in reducing mycotoxin production in simulated fungal growth media due to the changes linked to essential compounds content. The reduction ratio was 54.3% and 74.57% for total aflatoxins (AFs) and ochratoxin A (OCA) contents, respectively. These results reflect the microfluidizing improvement impact regarding the LGEO antibacterial, antifungal and anti-mycotoxigenic properties.

Purpose: The purpose of this study was to compare the antigenic potency and stability of tetanus and diphtheria (Td) vaccines when combined with aluminum phosphate (AlPO 4 ) and liposome adjuvants., Materials and Methods: In vitro and in vivo analyses were conducted using the single radial immunodiffusion method and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The Td vaccines were prepared with AlPO 4 adsorption and liposome-mediated delivery, and protein antigens were characterized using these methods., Results: The results revealed that the liposome-mediated Td vaccines exhibited higher immunogenicity compared to the AlPO 4 -adsorbed Td vaccines. Additionally, the liposome-mediated Td vaccines demonstrated higher stability as native antigens., Conclusion: This study highlights the importance of utilizing liposome adjuvants in vaccine development. The liposome-mediated Td vaccines showed enhanced immunogenicity and stability, making them a promising approach for improving vaccine efficacy. Understanding and optimizing adjuvant strategies can contribute to the development of effective vaccines against various diseases., Competing Interests: No potential conflict of interest relevant to this article was reported., (© Korean Vaccine Society.)

At high pressure, the pressure dependencies of the structural, electronic, optical, and thermoelectric properties of Fe 2 HfSi Heusler were calculated using the FP-LAPW method within the framework of the density functional theory. The calculations were carried out using the modified Becke-Johnson (mBJ) scheme. Our calculations showed that the Born mechanical stability criteria confirmed the mechanical stability in the cubic phase. Further, through Poisson and Pugh's ratios critical limits, the findings of the ductile strength were computed. At a pressure of 0 GPa, the indirect nature of the material may be deduced from the electronic band structures of Fe 2 HfSi as well as the estimations for its density of states. Under pressure, the real and imaginary dielectric function responses, optical conductivity, absorption coefficient, energy loss function, refractive index, reflectivity, and extinction coefficient were computed in the 0-12 eV range. Using semi-classical Boltzmann theory, a thermal response is also studied. As the pressure rises, the Seebeck coefficient decreases, while the electrical conductivity rises. The figure of merit ( ZT ) and Seebeck coefficients were determined at temperatures of 300 K, 600 K, 900 K, and 1200 K in order to better understand the thermoelectric properties of a material at these different temperatures. Despite the fact that the ideal Seebeck coefficient for Fe 2 HfSi was discovered at 300 K and was determined to be superior to that reported previously. Materials with a thermoelectric reaction has been shown to be suitable for reusing waste heat in systems. As a result, Fe 2 HfSi functional material may aid in the development of new energy harvesting and optoelectronic technologies., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Introduction: Type 2 diabetes mellitus (T2DM) is a major global health concern. It usually develops gradually and is frequently preceded by undetectable pre-diabetes mellitus (pre-DM) stage. The purpose of this study was to identify a novel set of seven candidate genes associated with the pathogenesis of insulin resistance (IR) and pre-DM, followed by their experimental validation in patients' serum samples., Methods: We used the bioinformatics tools and through a two-step process, we first identified and verified two mRNA candidate genes linked to insulin resistance molecular pathogenesis. Second, we identified a non-coding RNAs related to the selected mRNAs and implicated in the insulin resistance molecular pathways followed by pilot study for the RNA panel differential expression in 66 patients with T2DM, 49 individuals with prediabetes and 45 matched controls using real time PCR., Results: The levels of expression of TMEM173 and CHUK mRNAs, hsa-miR (-611, -5192, and -1976) miRNAs gradually increased from the healthy control group to the prediabetic group, reaching their maximum levels in the T2DM group (p <10-3), whereas the levels of expression of RP4-605O3.4 and AC074117.2 lncRNAs declined gradually from the healthy control group to the prediabetic group, reaching their lowest levels in the T2DM group (p <10-3). TMEM173, CHUK mRNAs, hsa&#95;miR (-611 & -1976) and RP4-605O3.4 lncRNA were useful in distinguishing insulin resistant from insulin sensitive groups. miR&#95;611 together with RP4-605O3.4 exhibited significant difference in good versus poor glycemic control groups., Discussion: The presented study provides an insight about this RNA based STING/NOD/IR associated panel that could be used for PreDM-T2DM diagnosis and also as a therapeutic target based on the differences of its expression level in the pre-DM and T2DM stages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ali, Kamel, Agwa, Hakeem, Meteini and Matboli.)

Camel milk is known as a source of nutritional and health supplements. It is known to be rich in peptides and functional proteins. One main issue facing it is related to its contamination, mainly with aflatoxins. The present study aimed to evaluate camel milk samples from different regions while trying to reduce its toxicity using safe approaches based on probiotic bacteria. Collected samples of camel milk were sourced from two main regions: the Arabic peninsula and North Africa. Samples were tested for their contents of aflatoxins (B 1 and M 1 ) using two techniques to ensure desired contamination levels. Additionally, feed materials used in camel foods were evaluated. Applied techniques were also tested for their validation. The antioxidant activity of camel milk samples was determined through total phenolic content and antioxidant activity assays. Two strains of probiotic bacteria ( Lactobacillus acidophilus NRC06 and Lactobacillus plantarum NRC21) were investigated for their activity against toxigenic fungi. The result revealed high contamination of aflatoxin M 1 for all samples investigated. Furthermore, cross-contamination with aflatoxin B 1 was recorded. Investigated bacteria were recorded according to their significant inhibition zones against fungal growth (11 to 40 mm). The antagonistic impacts were between 40% and 70% against toxigenic fungi. Anti-aflatoxigenic properties of bacterial strains in liquid media were recorded according to mycelia inhibition levels between 41 to 52.83% against Aspergillus parasiticus ITEM11 with an ability to reduce aflatoxin production between 84.39% ± 2.59 and 90.4% ± 1.32 from media. Bacteria removed aflatoxins from the spiked camel milk in cases involving individual toxin contamination.

Objective: Arabic gum Acacia (AG) is rich in fiber which improves lipid metabolism besides its antioxidant effect. Folium mori (FM) is a widely used herb due to its immunomodulatory, antimicrobial, and antioxidant activity. In the current study, we explore the antidiabetic, anti-inflammatory, as well as antioxidant activities of AG and FM in Streptozotocin (STZ), induced diabetic rats., Materials and Methods: STZ diabetic rats were orally administrated with metformin and/or a combination of AG and FM for 4 weeks. Glycemic levels, Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), cholesterol, triglycerides, urea, and creatinine were determined. Malondialdehyde (MDA), glutathione peroxidase (GPx), and Superoxide dismutase (SOD) were also evaluated. Gene expression and profile as well as immunohistopathological were also evaluated., Results: The results elicited no toxicological profile of both AG and FM. Plasma glucose level was decreased starting from 1st week to 4th week; besides, there was an improvement in glycated hemoglobin, insulin, and fructosamine. Liver and kidney damage markers were decreased in both AG and FM-treated rats. A significant increase in the antioxidant defense system and a decrease in oxidative stress markers were also observed. Gene expression analysis in brain tissues revealed a significant decrease in Interleukin beta 1 (IL-β1), Caspase 3 (Cas-3), and Transforming growth factor beta (TGF-β)., Conclusions: Oral treatment of metformin with AG and FM in STZ-injected rats could ameliorate protective pathways and can be one of the promising oral anti-diabetic herbal agents.