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Ahmed AH Abdellatif,1,2,* Fatma Ahmed,3,* Ahmed M Mohammed,2 Mansour Alsharidah,4 Amal Al-Subaiyel,1 Waad A Samman,5 Aisha A Alhaddad,5 Samiah Hamad Al-Mijalli,6 Mohammed A Amin,1,2 Hassan Barakat,7,8 Shaaban K Osman2,* 1Department of Pharmaceutics, College of Pharmacy, Qassim University, Qassim, 51452, Saudi Arabia; 2Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt; 3Department of Zoology, Faculty of Science, Sohag University, Sohag, 82524, Egypt; 4Department of Physiology, College of Medicine, Qassim University, Buraydah, 51452, Saudi Arabia; 5Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina, 42353, Saudi Arabia; 6Department of Biology, College of Sciences, Princess Nourah Bint Abdulrahman University, Riyadh, 11671, Saudi Arabia; 7Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, 51452, Saudi Arabia; 8Food Technology Department, Faculty of Agriculture, Benha University, Moshtohor, 13736, Egypt*These authors contributed equally to this workCorrespondence: Shaaban K Osman, Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt, Tel +2 01129059936, Fax +2-088-312191, Email Shaabanosman@azhar.edu.eg Ahmed AH Abdellatif, Department of Pharmaceutics, College of Pharmacy, Qassim University, Qassim, 51452, Saudi Arabia, Email a.abdellatif@qu.edu.saAbstract: The real problem in pharmaceutical preparation is drugs’ poor aqueous solubility, low permeability through biological membranes, and short biological t1/2. Conventional drug delivery systems are not able to overcome these problems. However, cyclodextrins (CDs) and their derivatives can solve these challenges. This article aims to summarize and review the history, properties, and different applications of cyclodextrins, especially the ability of inclusion complex formation. It also refers to the effects of cyclodextrin on drug solubility, bioavailability, and stability. Moreover, it focuses on preparing and applying gold nanoparticles (AuNPs) as novel drug delivery systems. It also studies the uses and effects of cyclodextrins in this field as novel drug carriers and targeting devices. The system formulated from AuNPs linked with CD molecules combines the advantages of both CD and AuNPs. Cyclodextrins benefit in increasing aqueous drug solubility, loading capacity, stability, and size control of gold NPs. Also, AuNPs are applied as diagnostic and therapeutic agents because of their unique chemical properties. Plus, AuNPs possess several advantages such as ease of detection, targeted and selective drug delivery, greater surface area, high loading efficiency, and higher stability than microparticles. In the present article, we tried to present the potential pharmaceutical applications of CD-derived AuNPs in biomedical applications including antibacterial, anticancer, gene-drug delivery, and various targeted drug delivery applications. Also, the article highlighted the role of CDs in the preparation and improvement of catalytic enzymes, the formation of self-assembling molecular print boards, the fabrication of supramolecular functionalized electrodes, and biosensors formation.Keywords: AuNPs, nanotechnology, drug delivery, drug targeting, inclusion complexes, cancer management

Aim: The severity of COVID-19 is influenced by uncontrolled hyper-inflammatory response with excessive release of many cytokines and chemokines. The understanding of the temporal change in the cytokine levels that underlies the diverse clinical presentations of COVID-19 can help in the prediction of the disease outcome and in the design of proper treatment strategies., Method: Data were collected from children (<18 years old) hospitalised with severe COVID-19 or severe MIS-C who were compared to a group of healthy control children. Patient demographics, clinical, laboratory data and cytokines profiles were evaluated. Blood samples were collected within 24 h of admission for all enrolled children and on Day 14., Results: Twenty-five children with severe COVID-19 and 23 cases with severe MIS-C were included in the study. The biochemical and inflammatory markers tend to be elevated in MIS-C group. There was a significant difference between studied cases and the control group in the following cytokines: G-CSF, IL-10, HMGB1, TNF-α, IL-6, IL-8 and INF-gamma (P < 0.05). While there was a significant difference between severe COVID-19 and MIS-C groups in the following cytokines at Day 1 of admission; IL-10, IL-6, IL-8 and INF-gamma; while at Day 14, there was a significant difference only for G-CSF, IL-10 and IL-6, all other cytokines were comparable., Conclusion: Our study underpinned patterns of cytokine response in severe COVID-19 and MIS-C. There is a significant upregulation in pro-inflammatory cytokines (mainly G-CSF, IL-10, HMGB1, TNF-α, IL-6, IL-8 and INF-gamma). These biomarkers that could imply on the severity rating and treatment strategies, should be preferentially assessed in SARS-CoV-2 associated immunological events., (© 2024 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Objective: There is a need to treat cancer cells with safe and natural nanoparticles to avoid the side effects of chemotherapeutic agents. Chamomile is considered a safe, natural plant with anticancer activity. We synthesize simple, inexpensive, and eco-friendly silver nanoparticles (SNs) using Chamomile (CHM) to tune their anticancer properties., Materials and Methods: SN-CHM was synthesized by reducing 1 mM silver nitrate aqueous solution in 100 mL with the aqueous ethanolic flower extract of CHM (18 mg/mL, w/v). The reaction proceeded overnight at 600 rpm and 28°C. SN-CHM was characterized for their % yield, average diameter, charge, morphology, and silver release. Moreover, SN-CHM was investigated for its antioxidant and anticancer activities at 200 µg/mL and 5 mg/ mL, respectively., Results: A 59.12% yield and a uniform SN-CHM size of 115 ± 3.1 nm with a ζ-potential of -27.67 ± (-3.92) mv were observed. The UV-visible absorption showed shifts from 379.5 to 383.5 nm for CHM and SN-CHM, respectively. Moreover, Ag+ was ultimately released from SN-CHM after 5 h. Fourier Transform Infrared Spectroscopy (FT-IR) showed characteristic absorption peaks of CHM and produced SN-CHM. Furthermore, SN-CHM showed moderate antioxidant activity. SN-CHM inhibited the % viability of SW620 and HT-29 cell lines at 20 μM. SN-CHM may also greatly upregulate the apoptotic gene BAX while considerably downregulating the anti-apoptotic genes BCL2 and BCL-Xl., Conclusions: CHM can be a safe soft drink, especially when conjugated with Ag ions as anticancer NPs. SN-CHM is considered potent anticancer activity against SW620, and HT-29 cell lines.

Background: Alzheimer's disease (AD) is a common neurodegenerative disorder without effective treatment. Thymoquinone (TQ) has demonstrated potential in exhibiting anti-inflammatory, anti-cancer, and antioxidant characteristics. Despite TQ's neuroprotection effect, there is a scarcity of information regarding its application in AD research, and its molecular trajectories remain ambiguous. Thus, the objective of the current investigation was to examine the potential beneficial effects and underlying mechanisms of TQ in scopolamine (SCOP)-induced neuronal injury to mimic AD in vivo model., Methods: Thirty mice were divided into normal, SCOP, and TQ groups. The Y-maze and pole climbing tests were performed to measure memory and motor performance. Afterwards, histopathological and immunohistochemical examinations were carried out. Furthermore, peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway-related proteins and genes were detected with an emphasis on the role of miR-9., Results: TQ has the potential to ameliorate cognitive deficits observed in SCOP-induced AD-like model, as evidenced by the improvement in behavioral outcomes, histopathological changes, modulation of the expression pattern of PPAR-γ downstream targets with a significant decrease in the deposition of amyloid beta (Aβ)., Conclusions: TQ provided meaningful multilevel neuroprotection through its anti-inflammatory and its PPAR-γ agonist activity. Consequently, TQ may possess a potential beneficial role against AD development.

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among the tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cancer cases. TrkA represents an attractive target for cancer treatment; however, currently available TrkA inhibitors face limitations in terms of resistance development and potential toxicity. Hence, the objective of this study was to identify new allosteric-approved inhibitors of TrkA that can overcome these challenges and be employed in cancer therapy. To achieve this goal, a screening of 9,923 drugs from the ChEMBL database was conducted to assess their repurposing potential using molecular docking. The top 49 drug candidates, exhibiting the highest docking scores (-11.569 to -7.962 kcal/mol), underwent MM-GBSA calculations to evaluate their binding energies. Delanzomib and tibalosin, the top two drugs with docking scores of -10.643 and -10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of -67.96 and -50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA. Based on these findings, we recommend further experimental evaluation of delanzomib and tibalosin to determine their potential as allosteric inhibitors of TrkA. These drugs have the potential to provide more effective and less toxic therapeutic alternatives. The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery., 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 Mukhtar, Abdelmoniem, Elrufaie, Edris, Ghaboosh, Mahgoub, Garelnabi, Osman, Sherif, Ashour, Ghazawi, Samman, Alhaddad, Bafail, Ibrahim, Mohamed and Alzain.)

Alzheimer's disease (AD) is a progressive neurological illness characterized by memory loss and cognitive deterioration. Dapagliflozin was suggested to attenuate the memory impairment associated with AD; however, its mechanisms were not fully elucidated. This study aims to examine the possible mechanisms of the neuroprotective effects of dapagliflozin against aluminum chloride (AlCl 3 )-induced AD. Rats were distributed into four groups: group 1 received saline, group 2 received AlCl 3 (70 mg/kg) daily for 9 weeks, and groups 3 and 4 were administered AlCl 3 (70 mg/kg) daily for 5 weeks. Dapagliflozin (1 mg/kg) and dapagliflozin (5 mg/kg) were then given daily with AlCl 3 for another 4 weeks. Two behavioral experiments were performed: the Morris Water Maze (MWM) and the Y-maze spontaneous alternation (Y-maze) task. Histopathological alterations in the brain, as well as changes in acetylcholinesterase (AChE) and amyloid β (Aβ) peptide activities and oxidative stress (OS) markers, were all evaluated. A western blot analysis was used for the detection of phosphorylated 5' AMP-activated protein kinase (p-AMPK), phosphorylated mammalian target of Rapamycin (p-mTOR) and heme oxygenase-1 (HO-1). Tissue samples were collected for the isolation of glucose transporters (GLUTs) and glycolytic enzymes using PCR analysis, and brain glucose levels were also measured. The current data demonstrate that dapagliflozin represents a possible approach to combat AlCl 3 -induced AD in rats through inhibiting oxidative stress, enhancing glucose metabolism and activating AMPK signaling.

Schistosomiasis is a neglected tropical disease with a significant socioeconomic impact. It is caused by several species of blood trematodes from the genus Schistosoma , with S. mansoni being the most prevalent. Praziquantel (PZQ) is the only drug available for treatment, but it is vulnerable to drug resistance and ineffective in the juvenile stage. Therefore, identifying new treatments is crucial. SmHDAC8 is a promising therapeutic target, and a new allosteric site was discovered, providing the opportunity for the identification of a new class of inhibitors. In this study, molecular docking was used to screen 13,257 phytochemicals from 80 Saudi medicinal plants for inhibitory activity on the SmHDAC8 allosteric site. Nine compounds with better docking scores than the reference were identified, and four of them (LTS0233470, LTS0020703, LTS0033093, and LTS0028823) exhibited promising results in ADMET analysis and molecular dynamics simulation. These compounds should be further explored experimentally as potential allosteric inhibitors of SmHDAC8.

Depsidones are a class of polyphenolic polyketides that have been proposed to be biosynthesized from oxidative coupling of esters of two polyketidic benzoic acid derivatives. They are principally encountered in fungi and lichens. In addition to their diversified structural features, they revealed varied bioactivities such as antimicrobial, antimalarial, cytotoxic, anti-inflammatory, anti- Helicobacter pylori , antimycobacterial, antihypertensive, anti-diarrheal, antidiabetic, phytotoxic, anti-HIV, anti-osteoclastogenic, and butyrylcholinesterase, tyrosinase, hyaluronidase, and acetylcholinesterase inhibition. The current work was targeted to provide an overview on the naturally reported depsidones from various sources in the period from 2018 to the end of 2022 including their structures, biosynthesis, sources, and bioactivities, as well as the reported structure-activity relationship and semisynthetic derivatives. A total of 172 metabolites with 87 references were reviewed. The reported findings unambiguously demonstrated that these derivatives could be promising leads for therapeutic agents. However, further in-vivo evaluation of their potential biological properties and mechanistic investigations are needed., Competing Interests: The authors declare that they have no competing interests., (© 2023 Khayat et al.)

The use of aromatase inhibitors is an established therapy for estrogen-dependent breast cancer in postmenopausal women. However, the only commercially available aromatase inhibitor, letrozole, is not highly selective; in addition to aromatase, it has an affinity for binding to desmolase, an enzyme involved in steroidogenesis, which explains the main side effects. Therefore, we designed new compounds based on the structure of letrozole. More than five thousand compounds were constructed based on the letrozole structure. Then, these compounds were screened for their binding ability toward the target protein, aromatase. Quantum docking, Glide docking, and ADME studies showed 14 new molecules with docking scores of ≤-7 kcal/mol, compared to the docking score of -4.109 kcal/mol of the reference, letrozole. Moreover, molecular dynamics (MD) and post-MD MM-GBSA calculations were calculated for the top three compounds, and the results supported in their interaction's stability. Finally, the density-functional theory (DFT) study applied to the top compound to study the interaction with gold nanoparticles revealed the most stable position for the interaction with the gold nanoparticles. The results of this study confirmed that these newly designed compounds could be useful starting points for lead optimization. Further in vitro and in vivo studies are recommended for these compounds to verify these promising results experimentally.

Non-Hodgkin's lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin's lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin's lymphoma cases develop at extranodal sites and the majority of them involve nodal and extranodal sites. The most common subtypes include follicular lymphoma, chronic/small lymphocytic leukaemia, mantel cell lymphoma, and marginal zone lymphoma. Umbralisib is one of the latest PI3Kδ inhibitors in clinical trials for several hematologic cancer indications. In this study, new umbralisib analogues were designed and docked to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR). This study resulted in eleven candidates, with strong binding to PI3Kδ with a docking score between -7.66 and -8.42 Kcal/mol. The docking analysis of ligand-receptor interactions between umbralisib analogues bound to PI3K showed that their interactions were mainly controlled by hydrophobic interactions and, to a lesser extent, by hydrogen bonding. In addition, the MM-GBSA binding free energy was calculated. Analogue 306 showed the highest free energy of binding with -52.22 Kcal/mol. To identify the structural changes and the complexes' stability of proposed ligands, molecular dynamic simulation was used. Based on this research finding, the best-designed analogue, analogue 306, formed a stable ligand-protein complex. In addition, pharmacokinetics and toxicity analysis using the QikProp tool demonstrated that analogue 306 had good absorption, distribution, metabolism, and excretion properties. Additionally, it has a promising predicted profile in immune toxicity, carcinogenicity, and cytotoxicity. In addition, analogue 306 had stable interactions with gold nanoparticles that have been studied using density functional theory calculations. The best interaction with gold was observed at the oxygen atom number 5 with -29.42 Kcal/mol. Further in vitro and in vivo investigations are recommended to be carried out to verify the anticancer activity of this analogue.

Aim: The aim of this study was to explore the effectiveness and safety of pentoxifylline as an adjuvant to risperidone in mitigating the negative symptoms in patients with chronic schizophrenia., Methods: In this randomized, placebo-controlled study, eighty outpatients with chronic schizophrenia were given risperidone for 8 weeks along with either pentoxifylline or a placebo. The positive and negative syndrome scale (PANSS) was used to assess patients at the start of the trial, as well as at 2, 4, 6, and 8 weeks. Pre- and posttreatment serum levels of cAMP, TNF-α-, and IL-6 were measured., Results: The pentoxifylline group revealed a significant effect for time-treatment interaction on PANSS-negative subscale scores (p < 0.001), PANSS general psychopathology subscale scores (p < 0.001), and PANSS total scores (p < 0.001), but not on PANSS-positive subscale scores (p = 0.169). Additionally, when compared to the placebo group, the pentoxifylline group demonstrated a statistically significant increase in cAMP serum level and a statistically significant decrease in TNF-α and IL-6 serum levels., Conclusion: Pentoxifylline adjunctive therapy with risperidone for 8 weeks was found to be promising in mitigating the negative symptoms in patients with chronic schizophrenia., Trial Registration Number: NCT04094207., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

The topical delivery of therapeutics is a promising strategy for managing skin conditions. Cyclooxygenase-2 (COX-2) inhibitors showed a possible target for chemoprevention and cancer management. Celecoxib (CXB) is a selective COX-2 inhibitor that impedes cell growth and generates apoptosis in different cell tumors. Herein, an investigation proceeded to explore the usefulness of nano lipid vesicles (transethosomes) (TES) of CXB to permit penetration of considerable quantities of the drug for curing skin cancer. The prepared nanovesicles were distinguished for drug encapsulation efficiency, vesicle size, PDI, surface charge, and morphology. In addition, FT-IR and DSC analyses were also conducted to examine the influence of vesicle components. The optimized formulation was dispersed in various hydrogel bases. Furthermore, in vitro CXB release and ex vivo permeability studies were evaluated. A cytotoxicity study proceeded using A431 and BJ1 cell lines. The expression alteration of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and DNA damage and fragmentation using qRT-PCR and comet assays were also investigated. Optimized CXB-TES formulation was spherically shaped and displayed a vesicle size of 75.9 ± 11.4 nm, a surface charge of -44.7 ± 1.52 mV, and an entrapment efficiency of 88.8 ± 7.2%. The formulated TES-based hydrogel displayed a sustained in vitro CXB release pattern for 24 h with an enhanced flux and permeation across rat skin compared with the control (free drug-loaded hydrogel). Interestingly, CXB-TES hydrogel has a lower cytotoxic effect on normal skin cells compared with TES suspension and CXB powder. Moreover, the level of expression of the CDKN2A gene was significantly ( p ≤ 0.01, ANOVA/Tukey) decreased in skin tumor cell lines compared with normal skin cell lines, indicating that TES are the suitable carrier for topical delivery of CXB to the cancer cells suppressing their progression. In addition, apoptosis demonstrated by comet and DNA fragmentation assays was evident in skin cancer cells exposed to CXB-loaded TES hydrogel formulation. In conclusion, our results illustrate that CXB-TES-loaded hydrogel could be considered a promising carrier and effective chemotherapeutic agent for the management of skin carcinoma.

CA (cyclosporine A) is a powerful immunosuppressing agent that is commonly utilized for treating various autoimmune illnesses and in transplantation surgery. However, its usage has been significantly restricted because of its unwanted effects, including nephrotoxicity. The pathophysiology of CA-induced kidney injury involves inflammation, apoptosis, tubular injury, oxidative stress, and vascular injury. Despite the fact that exact mechanism accountable for CA's effects is inadequately understood, ROS (reactive oxygen species) involvement has been widely proposed. At present, there are no efficient methods or drugs for treating CA-caused kidney damage. It is noteworthy that diverse natural products have been investigated both in vivo and in-vitro for their possible preventive potential in CA-produced nephrotoxicity. Various extracts and natural metabolites have been found to possess a remarkable potential for restoring CA-produced renal damage and oxidative stress alterations via their anti-apoptosis, anti-inflammatory, and antioxidative potentials. The present article reviews the reported studies that assess the protective capacity of natural products, as well as dietary regimens, in relation to CA-induced nephrotoxicity. Thus, the present study presents novel ideas for designing and developing more efficient prophylactic or remedial strategies versus CA passive influences.

The goal of this study was to see ethanolic extract of Ipomoea staphylina leaves could protect rats from D-GalN/LPS-induced AHF. Five groups (n=6) of male Wistar rats were created. Group I was given a normal control (1ml/kg); Group II was given D-GalN/LPS; Group III was given D-GalN/LPS + silymarin (100 mg/kg; p.o. ); Group IV was given D-GalN/LPS+ ethanolic extract of I. staphylina (100mg/kg); and Group V was given D-GalN/LPS+ ethanolic extract of I. staphylina (200mg/kg). All animals in groups II-V were given D-GalN/LPS (400mg/kg; and 30g/kg) on the 15 th day after being treated with silymarin or I. staphylina extract for 15 days. Blood was collected from all groups of animals 24 hours after D-GalN/LPS administration to conduct biochemical analysis. The levels of SGOT, SGPT, ALP, GGT and total bilirubin in animals pretreated with the extract were all considerably lower. In addition, the total protein content was considerably greater in the extract-treated mice. The extract led to a considerable decrease in LPO levels as well as a notable increase in SOD, CAT and GSH levels in liver tissue. The extract dramatically lowered TNF-α, IL-6, iNOS, NO and MPO levels in the liver tissue.