Computational analysis of 3D printing: Selecting the better among newly released materials.

Resin-based three-dimensional (3D) printing finds extensive application in the field of dentistry. Although studies of cytotoxicity, mechanical and physical properties have been conducted for newly released 3D printing resins such as Crowntec (Saremco), Temporary Crown Resin (Formlabs) and Crown & Bridge (Nextdent), the resistance of these materials to esterases in saliva has not been demonstrated at the molecular level. Therefore, in this study, the binding affinities and stability of these new 3D printing resins to the catalytic sites of esterases were investigated using molecular docking and molecular mechanics with Poisson-Bolzmann and surface area solvation (MM/PBSA) methods after active pocket screening. Toxicity predictions of the materials were also performed using ProTox-II and Toxtree servers. The materials were analyzed for mutagenicity, cytotoxicity, and carcinogenicity, and LD50 values were predicted from their molecular structures. The results indicated that out of the three novel 3D printing materials, Nexdent exhibited reduced binding affinity to esterases, indicating enhanced resistance to enzymatic degradation and possessing a superior toxicity profile.

Beyond Conventional Therapies: Molecular Dynamics of Alzheimer's Treatment through CLOCK/BMAL1 Interactions.

BACKGROUND: Alzheimer's Disease (AD) represents a neurodegenerative disorder characterized by cognitive and behavioral impairments significantly hindering social and occupational functioning. Melatonin, a hormone pivotal in regulating the body's intrinsic circadian rhythm, also acts as a catalyst in the breakdown of beta-amyloid deposits, offering a promising therapeutic approach for AD. The upregulation of Brain and Muscle ARNT-Like 1 (Bmal1) gene expression, stimulated by melatonin, emerges as a potential contributor to AD intervention. Current pharmacological interventions, such as FDA-approved cholinesterase inhibitors and the recently authorized monoclonal antibody, Lecanemab, are utilized in AD management. However, the connection between these medications and Bmal1 remains insufficiently explored.

Objective: This study aims to investigate the molecular effects of FDA-endorsed drugs on the CLOCK: Bmal1 dimer. Furthermore, considering the interactions between melatonin and Bmal1, this research explores the potential synergistic efficacy of combining these pharmaceutical agents with melatonin for AD treatment.

Methods: Using molecular docking and MM/PBSA methodologies, this research determines the binding affinities of drugs within the Bmal1 binding site, constructing interaction profiles.

Results: The findings reveal that, among FDA-approved drugs, galanthamine and donepezil demonstrate notably similar binding energy values to melatonin, interacting within the Bmal1 binding site through analogous amino acid residues and functional groups.

Conclusion: A novel therapeutic approach emerges, suggesting the combination of melatonin with Lecanemab as a monoclonal antibody therapy. Importantly, prior research has not explored the effects of FDA-approved drugs on Bmal1 expression or their potential for synergistic effects.

Is the BNT162b2 vaccine still effective against the latest variant: XBB.1.5?

Background: The XBB.1.5 sub-variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron now continues to spread rapidly due to the increased transmission rate as a result of increased affinity of the virus binding over the ACE-2 receptor - a gained property due to the mutation that occurred in spike protein. Aim: The protectivity of BNT162b2 antibodies produced in the serum of patients is an important parameter for preventing transmission. However, the affinity of the antibodies of patients vaccinated with BNT162b2 over the latest SARS-CoV-2 variant, XBB.1.5, is not well established. This study aimed to evaluate the efficacy of the BNT162b2 vaccine-induced antibody on XBB.1.5 by comparing the X-ray crystallographic structures and spike protein mutations of BA.5 and XBB.1.5 using in silico methods. Materials and Methods: Binding points and binding affinity values of the BNT162b2 antibody with BA.5 and XBB.1.5 spike protein were calculated using ClusPro 2.0 protein-protein docking and Discovery Studio 2021 Client software. Mutations in the genetic code of the spike protein for SARS-CoV-2 BA.5 and XBB.1.5 sub-variants were screened using the GISAID database. Results: Binding affinity values showed that BNT162b2 had higher negative values in the XBB.1.5 sub-variant than BA.5 at the mutation sites at the binding region. The results suggested that BNT162b2 may retain its activity despite mutations and conformational changes in the binding site of the XBB.1.5. Conclusion: The findings of this study shed light on the importance and usability of the current BNT162b2 vaccine for XBB.1.5 and future variants of concern.

An in silico investigation: Can melatonin serve as an adjuvant in NR1D1-linked chronotherapy for amyotrophic lateral sclerosis?

Chronobiology, which studies biological rhythms and their impacts on health, presents a potential avenue for treating amyotrophic lateral sclerosis. Clock gene-related therapies, focusing on genes responsible for regulating biological rhythms, may hold promise in the treatment. Among these clock genes, nuclear receptor subfamily 1 Group D member 1 (NR1D1) plays a vital role in neurodegenerative diseases. In this particular study, it was aimed to investigate the potential of FDA-approved drugs commonly used in amyotrophic lateral sclerosis treatment and melatonin, a hormone known for its role in regulating sleep-wake cycles, as ligands for clock gene-related therapy. The ligands were subjected to molecular docking and molecular dynamics simulation methods against the NR1D1 clock gene. These results suggested that combining melatonin with FDA-approved medications commonly used in the treatment might yield positive outcomes. This study provides preliminary data and lays the groundwork for future investigations involving in vitro (laboratory-based) and in vivo (animal or human-based) research on chronotherapy. In summary, this research highlights the potential of clock gene-related therapy utilizing melatonin in conjunction with FDA-approved drugs for amyotrophic lateral sclerosis treatment, offering insights into novel treatment strategies. The findings underscore the need for further studies to explore the effectiveness of this hypothetical approach in experimental and clinical settings.

Chronobiological Efficacy of Combined Therapy of Pelargonium Sidoides and Melatonin in Acute and Persistent Cases of COVID-19: A Hypothetical Approach.

Since the outbreak of the first SARS-CoV-2 epidemic in China, pharmacists have rapidly engaged and developed strategies for pharmaceutical care and supply. According to the guidelines of the International Pharmaceutical Federation (FIP), clinical pharmacists/hospital pharmacists, as members of care teams, play one of the most important roles in the pharmaceutical care of patients with COVID-19. During this pandemic, many immuno-enhancing adjuvant agents have become critical in addition to antivirals and vaccines in order to overcome the disease more easily. The liquid extract obtained from the Pelargonium sidoides plant is used for many indications such as colds, coughs, upper respiratory tract infections, sore throat, and acute bronchitis. The extract obtained from the roots of the plant has been observed to have antiviral and immunomodulatory activity. In addition to its anti-inflammatory and antioxidant effects, melatonin plays a role in suppressing the cytokine storm that can develop during COVID-19 infection. Knowing that the severity and duration of COVID-19 symptoms vary within 24 hours and/or in different time periods indicates that COVID-19 requires a chronotherapeutic approach. Our goal in the management of acute and long COVID is to synchronize the medication regimen with the patient's biological rhythm. This chapter provides a comprehensive review of the existing and emerging literature on the chronobiological use of Pelargonium sidoides and melatonin during acute and prolonged COVID-19 episodes.

Melatonin and REGN-CoV2 combination as a vaccine adjuvant for Omicron variant of SARS-CoV-2.

The omicron variant (B.529) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in late 2021, caused panic worldwide due to its contagiousness and multiple mutations in the spike protein compared to the Delta variant (B.617.2). There is currently no specific antiviral available to treat Coronavirus disease 2019 (COVID-19). However, studies on neutralizing monoclonal antibodies (mAb) developed to fight COVID-19 are growing and gaining traction. REGN-COV2 (Regeneron or imdevimab-casirivimab combination), which has been shown in recent studies to be less affected by Omicron's RBD (receptor binding domain) mutations among other mAb cocktails, plays an important role in adjuvant therapy against COVID-19. On the other hand, it is known that melatonin, which has antioxidant and immunomodulatory effects, can prevent a possible cytokine storm, and other severe symptoms that may develop in the event of viral invasion. Along with all these findings, we believe it is crucial to evaluate the use of melatonin with REGN-COV2, a cocktail of mAbs, as an adjuvant in the treatment and prevention of COVID-19, particularly in immunocompromised and elderly patients.

Synthesis and Apoptotic Activities of New 2(3H)-benzoxazolone Derivatives in Breast Cancer Cells.

BACKGROUND: 2(3H)-Benzoxazolone derivatives are preferential structural blocks in pharmacological probe designing with the possibility of modifications at various positions on the core structure. Benzoxazolones showed various biological activities such as analgesics, anti-inflammatory and anti-cancer. OBJECTIVE: In the present work, we have prepared new Mannich bases of 2(3H)-benzoxazolone derivatives and evaluated their cytotoxicities and proapoptotic properties in MCF-7 breast cancer cell line. METHODS: The structures of these compounds were characterized by FT-IR, elemental analysis, 1H and 13C NMR. Cytotoxicities of all the target compounds were investigated by MTT assay. Apoptotic properties of compounds were evaluated by immunocytochemistry using antibodies against caspase-3, cytochrome-c, FasL, and also TUNEL assay. RESULTS: These two novel compounds, 1 and 2, both have the same piperazine substituent on the nitrogen atom of benzoxazolone and the main difference in the structures of these compounds is the presence of Cl substituent at the 5- position of the benzoxazolone ring. MTT results showed that compounds 1 and 2 were effective in terms of reduction of cell viability at 100µM and 50µM concentration for 48h, respectively. As a result of immunohistochemical staining, Fas L and caspase-3 immunoreactivities were significantly increased in MCF-7 cells after treatment with compound 1. Additionally, caspase-3 and cytochrome-c immunoreactivities were also increased significantly in MCF-7 cells after treatment with compound 2. The number of TUNEL positive cells was significantly higher in MCF-7 cells when compared with the control group after treatment with both compounds 1 and 2. CONCLUSION: It could be concluded that N-substituted benzoxazolone derivatives increase potential anti-cancer effects and they could be promising novel therapeutic agents for chemotherapy.