SYNTHESIS, IN-SILICO BIOCHEMICAL PROPERTIES, AND IN-VITRO ANTIMICROBIAL ACTIVITY OF SOME FARMAZANS DERIVATIVES CONTAINING SULFONAMIDE MOIETY.

The low effectiveness of currently available antibiotics is driving efforts worldwide to create new antimicrobial medicines. We made several novel formazan chemicals, including sulfonamides, and assessed how well they may work against bacteria. Consequently, attempts were undertaken to combine the moieties of formazan and sulfonamide to produce new derivatives or more effective antibacterial drugs. Condensing sulphanilamide with benzaldehydes in the presence of glacial acetic acid and ethanol produced a Schiff base of sulphonamide, which when combined with substituted benzene diazonium chlorides (2a-g) during condensation yields formazan derivatives (3a-g). Based on analytical and spectral data (IR, 1HNMR, and mass), the structures of all the synthesized compounds were described, and they agree well with the suggested ones. Using Ciprofloxacin and Ketoconazole as reference medications, the Agar diffusion method was utilized to assess the antibacterial activity of the synthesized compounds by measuring the zone of inhibition against harmful strains of bacteria and fungi. In contrast to the norm, every molecule examined has demonstrated a notable level of antibacterial activity.

In Silico and ADMET Studies of Spiro-Quinazoline Compounds as Acetylcholine Esterase Inhibitors Against Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors are used in primary pharmacotherapy for numerous neurodegenerative conditions, providing their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, quinazoline derivatives have emerged as a compelling model for neurodegenerative disease treatment, showcasing promising pharmacological features. Their unique structural features and pharmacokinetic profiles have sparked interest in their potential efficacy and safety across diverse neurodegenerative disorders. The exposure of quinazoline derivatives as a potential therapeutic way underscores the imperative for continued research exploration. Their multifaceted mechanisms of action and ability to target various pathways implicated in neurodegeneration offer exciting prospects for developing novel, effective, and well-tolerated treatments. Further investigations into their pharmacological activities and precise therapeutic roles are essential to advance our understanding of neurodegenerative disease pathophysiology and promote the development of modern therapeutic strategies to address this critical medical challenge. METHODS: Quinazoline derivatives have gained eminent acetylcholinesterase (AChE) inhibitory activity. Their ability to effectively modulate AChE activity makes them promising candidates for treating neurological disorders, particularly Alzheimer's disease (AD). Their intricate molecular structures confer selectivity and affinity for AChE, offering potential for the development of novel therapeutic agents targeting cholinergic pathways. Hence, in this study, we designed, synthesized, and characterized a series of spiro[cycloalakane-1,2'-quinazoline derivatives (1-6) to assess their possible AChE inhibiting ability using docking into the active sites. RESULTS: The AChE inhibitory potential of spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) was explored via docking studies of the AChE active site. The findings revealed significant inhibitory activity and highlighted the promising nature of these derivatives. CONCLUSION: The synthesized spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) exhibited their notable potential as AChE inhibitors. The observed significant inhibitory activity suggested that these derivatives warrant further exploration as candidates for developing therapeutic agents in AChE inhibitory pathways. This study emphasizes the relevance of quinazoline derivatives in searching for novel treatments for neurological disorders, particularly associated with cholinergic dysfunction, and they could be a useful alternative therapeutic agent.

Antibacterial and Antibiofilm Potential of Chlorophyllin Against Streptococcus mutans In Vitro and In Silico.

BACKGROUND: Streptococcus mutans is a leading causative agent of dental caries and exerts pathogenicity by forming biofilms. Dental caries continues to be a significant public health issue worldwide, affecting an estimated 2.5 billion people, showing a 14.6% increase over the past decade. Herein, the antibacterial potential of Chlorophyllin extracted from Spinacia oleracea was evaluated against biofilm-forming S. mutans via in vitro and in silico studies. METHODOLOGY: The antimicrobial activity of chlorophyllin extract against S. mutans isolates was tested using the agar well diffusion method. Chlorophyllin extract was also tested against biofilm-forming isolates of S. mutans. Chlorophyllin was docked with the antigen I/II (AgI/II) protein of S. mutans to evaluate its antimicrobial mechanism. The chemical structure and canonical SMILES format of Chlorophyllin were obtained from PubChem. Additionally, adsorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses of Chlorophyllin were performed using ADMETlab 2.0 to assess its pharmacokinetic properties. RESULTS: An agar well diffusion assay revealed that all S. mutans isolates were susceptible to Chlorophyllin extract and showed a variety of inhibition zones ranging from 32 to 41 mm. Chlorophyllin reduces the biofilm strength of four isolates from strong to moderate and six from strong to weak. The antibiofilm potential of Chlorophyllin was measured by a reduction in the number of functional groups observed in the Fourier Transform Infrared Spectrometer (FTIR) spectra of the extracellular polymeric substance (EPS) samples. Chlorophyllin showed binding with AgI/II proteins of S. mutans, which are involved in adherence to the tooth surface and initiating biofilm formation. The ADMET analysis revealed that the safety of Chlorophyllin exhibited favorable pharmacokinetic properties. CONCLUSIONS: Chlorophyllin stands out as a promising antibacterial and antibiofilm agent against biofilm-forming S. mutans, and its safety profile highlights its potential suitability for further investigation as a therapeutic agent.

Public health implications of antibiotic resistance in sewage water: an epidemiological perspective.

The emergence and rapid spread of antibiotic resistance pose a major threat to global health, attributing to misuse and overuse of antibiotics resulting in antibiotics-resistant bacteria through natural mutation or transfer of resistance genes. A cross-sectional study was carried out, in which a total of 36 samples were systematically collected; of these, 26 were derived from the wastewater efflux and 10 from the receiving waters at several critical junctures along the Sutlej River. Herein, this study elucidated elevated levels of antibiotic resistance among bacterial isolates sourced from urban wastewater. Escherichia coli (E. coli) was the highest at 90% among the isolates, followed by Klebsiella pneumoniae (K. pneumoniae) at 58%, Pseudomonas aeruginosa (P. aeruginosa) at 55%, and Salmonella spp. at 53%. Many antibiotics were found to be more resistant including Ciproflaxacin, Co-Trimaxazole, Ampicillin and Tetracycline. Several antibiotic-resistance genes were found in isolated bacterial spp., such as Aminoglycosides (aadA), Sulfonamides (Sul1, Sul3), Tetracyclines (Tet (A/B/D)) and Cephalosporins (Bla_CTM X) at 41%, 35%, 29% and 12% respectively. Furthermore, the development of innovative wastewater treatment models and surveillance programs are crucial to counteract the dissemination of antibiotic resistance. To investigate the genetic determinants of antibiotic resistance, molecular analysis was performed, including DNA isolation, PCR amplification, and sequence analysis. The study helps investigate a diverse range of ARBs and ARGs in wastewater, which highlights the need of better laws for antibiotic usage and wastewater treatment processes. This investigation also stresses on regular monitoring of ARBs and ARGs in sewage wastewater. Through proactive interventions and sustained scientific inquiry, we can strive toward preserving environmental integrity and public health for successive generations.

Patterns of the Leukemia Records that were Referred to the Regional Laboratory in Makkah, Saudi Arabia.

BACKGROUND: Leukemia is the fifth most common cancer in Saudi Arabia. The aim of this study was to assess the various patterns of leukemia associated with age, gender, and nationality in this region. METHODS: This cross-sectional study was conducted at the regional laboratory in Makkah, Saudi Arabia, from April to November 2023. Descriptive statistics were presented as frequencies and percentages by using the GraphPad Prism software. RESULTS: This study included 107 patients, and the results showed that leukemia cases were higher in males than females and more prevalent in older patients (above 50 years of age). Overall, acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) were the most common types of leukemia among Saudi patients. In addition, AML was the most prevalent type of leukemia in males and females, followed by ALL. Data also revealed that ALL was the most common type in the younger population, whereas AML was highly prevalent in older patients. CONCLUSIONS: In conclusion, this study provides valuable information about the patterns of leukemia reported at the regional laboratory in Makkah and will help in designing management and preventive approaches for these patients. This epidemiological investigation is also valuable for establishing proper medical databases.

Bacterial diseases of Asian sea bass (Lates calcarifer): A review for health management strategies and future aquaculture sustainability.

The advent of aquaculture has been one of the most significant shifts in world food supply during the last century. Aquaculture has rapidly expanded and become a global food industry, spurred by population expansion, increased seafood consumption, and decreased captured fisheries. Nonetheless, the exponential growth of aquaculture has emerged as a significant contributor to anthropogenic changes. Unexpectedly, the result has focused in the emergence and spread of new diseases. The Asian sea bass (Lates calcarifer) is an economically important species in aquaculture, contributing significantly to the global seafood market. However, bacterial diseases have emerged as a major concern, affecting both wild and cultured populations of this species. The most prevalent bacterial pathogens are streptococcus, vibriosis, nocardiosis, tenacibaculosis, and pot-belly disease. Therefore, this review aims to comprehensively analyze both emerging and non-emerging bacterial diseases affecting L. calcarifer and explore potential management approaches for their control. Through an extensive literature survey and critical evaluation of research findings, this review highlights the current understanding of bacterial diseases in L. calcarifer and proposes strategies for better disease management. In addition, this review looks at the rise and characteristics of aquaculture, the major bacterial pathogens of L. calcarifer and their effects, and the specific attributes of disease emergence in an aquatic rather than terrestrial context. It also considers the potential for future disease emergence in L. calcarifer due to aquaculture expansion and climate changes.

Utilizing a Fe3O4 Magnetite Nanoparticle for Anode Modification in a Microbial Desalination Cell to Treat Saltwater.

The microbial desalination cell (MDC) is a bio-electrochemical system that exhibits the ability to oxidize organic compounds, produce energy, and decrease the saline concentrations within the desalination chamber. The selective removal of ions from the desalination chamber is significantly influenced by the anion and cation exchange membranes. In this study, a three-chamber microbial desalination cell was developed to treat seawater using a synthesize Fe3O4 magnetite nanoparticle (MNP)-modified anode. The impact of different performance parameters, such as temperature, pH, and concentrations of NPs, has been investigated in order to assess the performance of three-chamber MDCs in terms of energy recovery and salt removal. The evaluation criteria of the system included multiple factors such as chemical oxygen demand (COD), Coulombic efficiency (CE), desalination efficiency, as well as system aspects including voltage generation and power density. The highest COD% removal efficiency was 74% at 37 °C, pH = 7, and 30 g/L salt concentration with an optimized NPs concentration of 2.0 mg/cm2 impregnated on anode. The maximum Coulombic efficiency was 10.3% with the maximum power density of 4.3 W/m3. The effect of the nanoparticle concentration impregnated on the anode was clarified by the primary factor of analysis. This research has revealed consistent patterns in the enhancement of voltage generation, COD, and Coulombic efficiencies when incorporating higher concentrations of nanoparticles on the anode at a certain point.

Alkaline protease functionalized hydrothermal synthesis of novel gold nanoparticles (ALPs-AuNPs): A new entry in photocatalytic and biological applications.

Researchers are consistently investigating novel and distinctive methods and materials that are compatible for human life and environmental conditions This study aimed to synthesize gold nanoparticles (ALPs-AuNPs) using for the first time an alkaline protease (ALPs) derived from Phalaris minor seed extract. A series of physicochemical techniques were used to inquire the formation, size, shape and crystalline nature of ALPs-AuNPs. The nanoparticles' ability to degrade methylene blue (MB) through photocatalysis under visible light irradiation was assessed. The findings demonstrated that ALPs-AuNPs exhibited remarkable efficacy by destroying 100 % of MB within a mere 30-minute irradiation period. In addition, the ALPs-AuNPs demonstrated remarkable effectiveness in inhibiting the growth of gram-positive (S. aureus) and gram-negative (E. coli) bacteria. The inhibition zones examined against the two bacterial strains were 23(±0.3) mm and 19(±0.4); 13(±0.3) mm and 11(±0.5) mm under light and dark conditions respectively. The ALPs-AuNPs exhibited significant antioxidant activity by effectively scavenging 88 % of stable and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. As a result, the findings demonstrated that the environmentally friendly ALPs-AuNPs showed a strong potential for MB degradation and bacterial pathogen treatment.

Genetic variants associated with dengue hemorrhagic fever. A systematic review and meta-analysis.

Dengue hemorrhagic fever (DHF) is a severe condition resulting from the dengue virus, with four serotypes known as DEN-1, DEN-2, DEN-3, and DEN-4. Genetic variations play a crucial role in influencing susceptibility to DHF. Therefore, this investigation conducted a meta-analysis to uncover genetic changes that might have remained undetected in individual studies due to small sample sizes or methodological differences. Among 2212 initially identified studies, 23 were deemed suitable for analysis based on PRISMA guidelines. Toll-like receptors (TLR) and CD209 showed significant association with DHF (odds ratios: TLR=0.56, CD209 =0.55), indicating protective effects. However, tumor necrosis factor (TNF) and human leukocyte antigen (HLA) did not exhibit a statistically significant relationship with DHF. This study emphasizes the relevance of TLR and CD209 in DHF susceptibility and resistance across diverse geographical locations.

The Association of Vitamin D, Growth/Differentiation Factor 5 (GDF-5) Gene Polymorphism, and Serum GDF-5 Protein in Obese Patients With Knee Osteoarthritis.

Background and objective Osteoarthritis (OA) is influenced by genetics and environmental factors, including vitamin D deficiency. This study aimed to investigate the association between vitamin D levels, growth/differentiation factor 5 (GDF-5) gene polymorphism, and serum GDF-5 in obese females with knee OA (KOA) in Saudi Arabia. Methodology The study enrolled 60 female patients with OA and 60 healthy females as controls. Blood samples were collected to evaluate the GDF-5 T>C (rs143383) polymorphism using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The study also measured serum levels of vitamin D, GDF-5, calcium, uric acid, lipid profiles, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), and assessed the participants' BMI. Results The study demonstrated that KOA patients had reduced vitamin D levels in their bodies, along with GDF-5 and calcium. However, they had increased levels of uric acid, lipid profile, CRP, and ESR. Strong correlations were observed between vitamin D levels, lipid profile, CRP, ESR, BMI, GDF-5 gene polymorphisms, and GDF-5 protein. Genotype analysis showed KOA patients had TT (30%), TC (50%), and CC (20%) genotypes, while the control group showed TT (22%), TC (35%), and CC (43%) genotypes. Allele analysis revealed a noteworthy association between the T allele and KOA; the C allele was more common in the control group. Conclusions The study findings provide valuable insights into the association of vitamin D levels with GDF-5 T>C (rs143383) polymorphism, GDF-5 protein, and inflammatory markers in obese Saudi females with KOA. These findings suggest potential associations between these biomarkers and the pathogenesis or progression of KOA.

The Prevalence of Transfusion-Transmitted Diseases Among Blood Donors in the Central Blood Bank in Makkah, Saudi Arabia.

Background This study aimed to analyze the health and demographic characteristics of blood donors in Makkah, Saudi Arabia, and assess the prevalence and correlation of two markers related to hepatitis B infection: hepatitis B virus surface antigen (HBsAg) and anti-hepatitis B virus surface antibody (HBsAb). Materials and methods The study used a retrospective design and collected data from the Central Blood Bank in Makkah, Saudi Arabia, in 2022. The sample size was 7,875 blood donors. The study used various methods, such as serological testing, nucleic acid testing (NAT), and statistical analysis. The data were analyzed using Pearson correlation to examine the relationships between different variables. Results The predominant age group was 29-39 years, accounting for 46.9% of the total donors. In terms of blood types, O+ve was the most common, representing 40.3% of the donors. The investigation into infectious markers revealed overall low levels of reactivity among donors. For HBsAg, a marker of active hepatitis B infection, only 0.36% of the units were reactive. Conversely, the anti-HBsAb, which indicates immunity to hepatitis B, was reactive in 6.83% of the units. The correlation analysis illuminated some critical relationships. The total number of units tested had a statistically significant, albeit weak, positive relationship with HBsAg reactivity, shown by a Pearson correlation coefficient of 0.030 and a p-value of 0.008. Conversely, the total number of units tested and anti-HBsAb reactivity showed a moderate negative correlation, with a Pearson correlation coefficient of -0.437 and a p-value of less than 0.001. However, no significant correlation was identified between HBsAg and anti-HBsAb reactivity, indicating that active infection and immunity status might not be directly linked. Conclusion This extensive study provides in-depth insights into the sociodemographic characteristics of blood donors and the prevalence of key infectious markers within this population. It underlines the imperative of rigorous screening of blood units, particularly given the low immunity levels to hepatitis B identified. Also, the study showed the importance of screening blood units and vaccinating people against hepatitis B. It also suggested the need for more research on blood safety and infection-immunity relationships.

Diverse Pharmacological Potential of different Substituted Pyrazole Derivatives.

The chemistry of heterocyclic compounds has been a topic of research interest. Some five-membered heterocyclic compounds have been the subject of extensive research due to their different types of pharmacological effects. The five-membered nitrogen-containing heterocyclic compounds pyrazole, pyrazoline, and pyrazolone derivatives have a lot of interest in the fields of medical and agricultural chemistry due to their diverse spectrum of therapeutic activities. Various substituted pyrazole, pyrazoline, and pyrazolone compounds exhibited diverse pharmacological effects like Anti-microbial, anti-inflammatory, anti-tubercular, anti-fungal, anti-malarial, anti-di-abetic, diuretic, anti-depressant, anticonvulsant, antioxidant, anti-leishmanial, antidiabetic, and antiviral, etc. In recent decades, the synthesis of numerous pyrazole, pyrazoline, and pyrazolone derivatives by different synthetic methods as well as research into their chemical and biological behavior have become more important. This review focuses on synthetic methods of the pyrazole, pyrazoline, and pyrazolone derivatives, which have significant biological properties and a variety of applications.

Green Synthetic Methods of Oxazine and Thiazine Scaffolds as Promising Medicinal Compounds: A Mini-Review.

Medical researchers have paid close attention to the green synthesis of oxazine and thiazine derivatives since they provided a lead molecule for the creation of numerous possible bioactive compounds. This review provides more information on green synthesis, which will be very helpful to researchers in creating the most effective, affordable, and clinically significant thiazine and oxazine derivatives that are anticipated to have strong pharmacological effects. This has resulted in the identification of several substances with a wide range of intriguing biological functions. This article's goal is to examine the numerous green chemical processes used to create oxazine and thiazine derivatives and their biological activity. We anticipate that researchers interested in oxazine and thiazine chemicals will find this material to be useful. We anticipate that medicinal chemists looking for new active medicinal components for drug discovery and advance progress will find this review of considerable interest.

Isoform switching leads to downregulation of cytokine producing genes in estrogen receptor positive breast cancer.

Objective: Estrogen receptor breast cancer (BC) is characterized by the expression of estrogen receptors. It is the most common cancer among women, with an incidence rate of 2.26 million cases worldwide. The aim of this study was to identify differentially expressed genes and isoform switching between estrogen receptor positive and triple negative BC samples. Methods: The data were collected from ArrayExpress, followed by preprocessing and subsequent mapping from HISAT2. Read quantification was performed by StringTie, and then R package ballgown was used to perform differential expression analysis. Functional enrichment analysis was conducted using Enrichr, and then immune genes were shortlisted based on the ScType marker database. Isoform switch analysis was also performed using the IsoformSwitchAnalyzeR package. Results: A total of 9,771 differentially expressed genes were identified, of which 86 were upregulated and 117 were downregulated. Six genes were identified as mainly associated with estrogen receptor positive BC, while a novel set of ten genes were found which have not previously been reported in estrogen receptor positive BC. Furthermore, alternative splicing and subsequent isoform usage in the immune system related genes were determined. Conclusion: This study identified the differential usage of isoforms in the immune system related genes in cancer cells that suggest immunosuppression due to the dysregulation of CXCR chemokine receptor binding, iron ion binding, and cytokine activity.

Application of nanomaterials as potential quorum quenchers for disease: Recent advances and challenges.

Chemical signal molecules are used by bacteria to interact with one another. Small hormone-like molecules known as autoinducers are produced, released, detected, and responded to during chemical communication. Quorum Sensing (QS) is the word for this procedure; it allows bacterial populations to communicate and coordinate group behavior. Several research has been conducted on using inhibitors to prevent QS and minimize the detrimental consequences. Through the enzymatic breakdown of the autoinducer component, by preventing the formation of autoinducers, or by blocking their reception by adding some compounds (inhibitors) that can mimic the autoinducers, a technique known as "quorum quenching" (QQ) disrupts microbial communication. Numerous techniques, including colorimetry, electrochemistry, bioluminescence, chemiluminescence, fluorescence, chromatography-mass spectroscopy, and many more, can be used to test QS/QQ. They all permit quantitative and qualitative measurements of QS/QQ molecules. The mechanism of QS and QQ, as well as the use of QQ in the prevention of biofilms, are all elaborated upon in this writing, along with the fundamental study of nanoparticle (NP)in QQ. Q.

Eco-friendly synthesized nanoparticles as antimicrobial agents: an updated review.

Green synthesis of NPs has gained extensive acceptance as they are reliable, eco-friendly, sustainable, and stable. Chemically synthesized NPs cause lung inflammation, heart problems, liver dysfunction, immune suppression, organ accumulation, and altered metabolism, leading to organ-specific toxicity. NPs synthesized from plants and microbes are biologically safe and cost-effective. These microbes and plant sources can consume and accumulate inorganic metal ions from their adjacent niches, thus synthesizing extracellular and intracellular NPs. These inherent characteristics of biological cells to process and modify inorganic metal ions into NPs have helped explore an area of biochemical analysis. Biological entities or their extracts used in NPs include algae, bacteria, fungi, actinomycetes, viruses, yeasts, and plants, with varying capabilities through the bioreduction of metallic NPs. These biosynthesized NPs have a wide range of pharmaceutical applications, such as tissue engineering, detection of pathogens or proteins, antimicrobial agents, anticancer mediators, vehicles for drug delivery, formulations for functional foods, and identification of pathogens, which can contribute to translational research in medical applications. NPs have various applications in the food and drug packaging industry, agriculture, and environmental remediation.

Diverse pharmacological potential of pyridazine analogs against various diseases.

Pyridazinone analogs possess diverse types of pharmacological activities, such as anticancer, antimicrobial, anticonvulsant, analgesic, anti-inflammatory, antioxidant, antihypertensive, antisecretory, antiulcer, and other useful pharmacological activities. They also possess cyclooxygenase (COX) inhibitors, dipeptidyl peptidase inhibitors, phosphodiesterase inhibitors, glutamate transporter activators, adenosine receptor antagonists, serotonin receptors antagonists, lipooxygenase, cholinesterase, vasodilator, and anesthetics. Pyridazine rings are the essential structure for some marketed drugs, such as pimobendan, levosimendan as a cardiotonic drug, and emorfozan as an analgesic and anti-inflammatory (Non-steroidal anti-inflammatory drug) agent. So, researchers all over the world have paid attention to synthesizing various pyridazinone compounds mainly due to the ease of design and synthesis of different analogs and variables in the pharmacological responses. This review article focuses on the pharmacological activities of different pyridazine analogs.

Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need.

Rett syndrome (RTT) is a rare disability causing female-oriented pediatric neurodevelopmental unmet medical need. RTT was recognized in 1966. However, over the past 56 years, the United States Food and Drug Administration (USFDA) has authorized no effective treatment for RTT. Recently, Trofinetide was approved by the USFDA on 10 March 2023 as the first RTT treatment. This article underlines the pharmaceutical advancement, patent literature, and prospects of Trofinetide. The data for this study were gathered from the PubMed database, authentic websites (Acadia Pharmaceuticals, Neuren Pharmaceuticals, and USFDA), and free patent databases. Trofinetide was first disclosed by Neuren Pharmaceuticals in 2000 as a methyl group containing analog of the naturally occurring neuroprotective tripeptide called glycine-proline-glutamate (GPE). The joint efforts of Acadia Pharmaceuticals and Neuren Pharmaceuticals have developed Trofinetide. The mechanism of action of Trofinetide is not yet well established. However, it is supposed to improve neuronal morphology and synaptic functioning. The patent literature revealed a handful of inventions related to Trofinetide, providing excellent and unexplored broad research possibilities with Trofinetide. The development of innovative Trofinetide-based molecules, combinations of Trofinetide, patient-compliant drug formulations, and precise MECP2-mutation-related personalized medicines are foreseeable. Trofinetide is in clinical trials for some neurodevelopmental disorders (NDDs), including treating Fragile X syndrome (FXS). It is expected that Trofinetide may be approved for treating FXS in the future. The USFDA-approval of Trofinetide is one of the important milestones for RTT therapy and is the beginning of a new era for the therapy of RTT, FXS, autism spectrum disorder (ASD), brain injury, stroke, and other NDDs.

Computational formulation of a multiepitope vaccine unveils an exceptional prophylactic candidate against Merkel cell polyomavirus.

Merkel cell carcinoma (MCC) is a rare neuroendocrine skin malignancy caused by human Merkel cell polyomavirus (MCV), leading to the most aggressive skin cancer in humans. MCV has been identified in approximately 43%-100% of MCC cases, contributing to the highly aggressive nature of primary cutaneous carcinoma and leading to a notable mortality rate. Currently, no existing vaccines or drug candidates have shown efficacy in addressing the ailment caused by this specific pathogen. Therefore, this study aimed to design a novel multiepitope vaccine candidate against the virus using integrated immunoinformatics and vaccinomics approaches. Initially, the highest antigenic, immunogenic, and non-allergenic epitopes of cytotoxic T lymphocytes, helper T lymphocytes, and linear B lymphocytes corresponding to the virus whole protein sequences were identified and retrieved for vaccine construction. Subsequently, the selected epitopes were linked with appropriate linkers and added an adjuvant in front of the construct to enhance the immunogenicity of the vaccine candidates. Additionally, molecular docking and dynamics simulations identified strong and stable binding interactions between vaccine candidates and human Toll-like receptor 4. Furthermore, computer-aided immune simulation found the real-life-like immune response of vaccine candidates upon administration to the human body. Finally, codon optimization was conducted on the vaccine candidates to facilitate the in silico cloning of the vaccine into the pET28+(a) cloning vector. In conclusion, the vaccine candidate developed in this study is anticipated to augment the immune response in humans and effectively combat the virus. Nevertheless, it is imperative to conduct in vitro and in vivo assays to evaluate the efficacy of these vaccine candidates thoroughly. These evaluations will provide critical insights into the vaccine's effectiveness and potential for further development.

In Silico Identification of Natural Product-Based Inhibitors Targeting IL-1ß/IL-1R Protein-Protein Interface.

IL-1ß mediates inflammation and regulates immune responses, cell proliferation, and differentiation. Dysregulation of IL-1ß is linked to inflammatory and autoimmune diseases. Elevated IL-1ß levels are found in patients with severe COVID-19, indicating its excessive production may worsen the disease. Also, dry eye disease patients show high IL-1ß levels in tears and conjunctival epithelium. Therefore, IL-1ß signaling is a potential therapeutic targeting for COVID-19 and aforementioned diseases. No small-molecule IL-1ß inhibitor is clinically approved despite efforts. Developing such inhibitors is highly desirable. Herein, a docking-based strategy was used to screen the TCM (Traditional Chinese Medicine) database to identify possible IL-1ß inhibitors with desirable pharmacological characteristics by targeting the IL-1ß/IL-1R interface. Primarily, the docking-based screening was performed by selecting the crucial residues of IL-1ß interface to retrieve the potential compounds. Afterwards, the compounds were shortlisted on the basis of binding scores and significant interactions with the crucial residues of IL-1ß. Further, to gain insights into the dynamic behavior of the protein-ligand interactions, MD simulations were performed. The analysis suggests that four selected compounds were stabilized in an IL-1ß pocket, possibly blocking the formation of an IL-1ß/IL-1R complex. This indicates their potential to interfere with the immune response, making them potential therapeutic agents to investigate further.