A computational approach for structural and functional analyses of disease-associated mutations in the human CYLD gene.

Tumor suppressor cylindromatosis protein (CYLD) regulates NF-κB and JNK signaling pathways by cleaving K63-linked poly-ubiquitin chain from its substrate molecules and thus preventing the progression of tumorigenesis and metastasis of the cancer cells. Mutations in CYLD can cause aberrant structure and abnormal functionality leading to tumor formation. In this study, we utilized several computational tools such as PANTHER, PROVEAN, PredictSNP, PolyPhen-2, PhD-SNP, PON-P2, and SIFT to find out deleterious nsSNPs. We also highlighted the damaging impact of those deleterious nsSNPs on the structure and function of the CYLD utilizing ConSurf, I-Mutant, SDM, Phyre2, HOPE, Swiss-PdbViewer, and Mutation 3D. We shortlisted 18 high-risk nsSNPs from a total of 446 nsSNPs recorded in the NCBI database. Based on the conservation profile, stability status, and structural impact analysis, we finalized 13 nsSNPs. Molecular docking analysis and molecular dynamic simulation concluded the study with the findings of two significant nsSNPs (R830K, H827R) which have a remarkable impact on binding affinity, RMSD, RMSF, radius of gyration, and hydrogen bond formation during CYLD-ubiquitin interaction. The principal component analysis compared native and two mutants R830K and H827R of CYLD that signify structural and energy profile fluctuations during molecular dynamic (MD) simulation. Finally, the protein-protein interaction network showed CYLD interacts with 20 proteins involved in several biological pathways that mutations can impair. Considering all these in silico analyses, our study recommended conducting large-scale association studies of nsSNPs of CYLD with cancer as well as designing precise medications against diseases associated with these polymorphisms.

Novel supramolecular luminescent metallogels containing Tb(iii) and Eu(iii) ions with benzene-1,3,5-tricarboxylic acid gelator: advancing semiconductor applications in microelectronic devices.

A novel strategy was employed to create supramolecular metallogels incorporating Tb(iii) and Eu(iii) ions using benzene-1,3,5-tricarboxylic acid (TA) as a gelator in N,N-dimethylformamide (DMF). Rheological analysis demonstrated their mechanical robustness under varying stress levels and angular frequencies. FESEM imaging revealed a flake-like hierarchical network for Tb-TA and a rod-shaped architecture for Eu-TA. EDX analysis confirmed essential chemical constituents within the metallogels. FT-IR, PXRD, Raman spectroscopy, and thermogravimetric analysis assessed their gelation process and material properties, showing semiconducting characteristics, validated by optical band-gap measurements. Metal-semiconductor junction-based devices integrating Al metal with Tb(iii)- and Eu(iii)-metallogels exhibited non-linear charge transport akin to a Schottky diode, indicating potential for advanced electronic device development. Direct utilization of benzene-1,3,5-tricarboxylic acid and Tb(iii)/Eu(iii) sources underscores their suitability as semiconducting materials for device fabrication. This study explores the versatile applications of Tb-TA and Eu-TA metallogels, offering insights for material science researchers.

Drug Repositioning Using Computer-aided Drug Design (CADD).

Drug repositioning is a method of using authorized drugs for other unusually complex diseases. Compared to new drug development, this method is fast, low in cost, and effective. Through the use of outstanding bioinformatics tools, such as computer-aided drug design (CADD), computer strategies play a vital role in the re-transformation of drugs. The use of CADD's special strategy for target-based drug reuse is the most promising method, and its realization rate is high. In this review article, we have particularly focused on understanding the various technologies of CADD and the use of computer-aided drug design for target-based drug reuse, taking COVID-19 and cancer as examples. Finally, it is concluded that CADD technology is accelerating the development of repurposed drugs due to its many advantages, and there are many facts to prove that the new ligand-targeting strategy is a beneficial method and that it will gain momentum with the development of technology.

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.

Evaluation of inflammatory cytokines in drug-naïve major depressive disorder: A systematic review and meta-analysis.

Objective: Altered levels of peripheral inflammatory and proinflammatory cytokine markers affect the different clinical stages of major depressive disorder (MDD). A concrete understanding of the causal mechanism of MDD is a prerequisite in developing treatment strategies and preventive plans. Here we aimed to conduct an updated systematic review and meta-analysis of studies assessing the association of C-reactive protein (CRP), INF-γ, MCP-1, and TNF-α in the peripheral fluid of drug-naïve MDD patients and healthy controls (HCs). Methods: We extracted articles from PubMed, ProQuest, PsycINFO, Web of Science, and Scopus databases from inception until 14 February 2021, to find relevant studies. In this meta-analysis, we included a total of 23 eligible studies (1,366 MDD patients and 1,342 controls) in the final meta-analysis. The Cochran's chi-square Q-test and I2-index were applied to measure the heterogeneity and inconsistency of all combined results. We selected a random-effect model during the analysis and measured publication biases using the funnel plot. We performed Bonferroni adjustment for multiple testing. Results: We found a high level of TNF-α in MDD patients than in control subjects Standardized Mean Difference (SMD) with a random-effects model: 1.04, 95% CI: 0.69-1.39, z = 5.84, p < 0.001). The levels of CRP (SMD with a random-effects model: 0.18, 95% CI: -0.85-1.23, z = 0.35, p = 0.73), INF-ɤ (SMD with a random-effects model: -0.05, 95% CI: -2.72-2.62, z = 0.03, p = 0.97), and MCP-1 (SMD with a random-effects model: 0.70, 95% CI: -0.09-1.49, z = 1.73, p = 0.08) were not significantly varies between MDD patients and HCs. Conclusion: The present study findings suggest the upregulated level of peripheral TNF-α but not CRP, INF-γ, and MCP-1 involve in depression. The elevated inflammatory cytokines confirmed the inflammatory state of depression. Therefore, inflammatory cytokines might serve as potential risk assessment markers in MDD.

Cyclodextrin nanoparticles in targeted cancer theranostics.

The field of cancer nanotheranostics is rapidly evolving, with cyclodextrin (CD)-based nanoparticles emerging as a promising tool. CDs, serving as nanocarriers, have higher adaptability and demonstrate immense potential in delivering powerful anti-cancer drugs, leading to promising and specific therapeutic outcomes for combating various types of cancer. The unique characteristics of CDs, combined with innovative nanocomplex creation techniques such as encapsulation, enable the development of potential theranostic treatments. The review here focuses mainly on the different techniques administered for effective nanotheranostics applications of CD-associated complex compounds in the domain of cancer treatments. The experimentations on various loaded drugs and their complex conjugates with CDs prove effective in in vivo results. Various cancers can have potential nanotheranostics cures using CDs as nanoparticles along with a highly efficient process of nanocomplex development and a drug delivery system. In conclusion, nanotheranostics holds immense potential for targeted drug delivery and improved therapeutic outcomes, offering a promising avenue for revolutionizing cancer treatments through continuous research and innovative approaches.

FDA Approval Summary: Mirvetuximab Soravtansine-Gynx for FRα-Positive, Platinum-Resistant Ovarian Cancer.

On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9-41.6] with a median duration of response of 6.9 months (95% CI, 5.6-9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx.

Potential Drug-Drug Interactions Between Anti-Cancer Drugs and Other Medications in Lung Cancer Patients: A Retrospective Study.

BACKGROUND: Cancer patients are more vulnerable to developing drug-drug interactions as multiple medications are administered concomitantly with cytotoxic agents to treat the underlying comorbidities. These drug-drug interactions often receive less medical attention and consequently are associated with adverse clinical outcomes. OBJECTIVE: We intended to comprehensively characterize the drug-drug interactions among anticancer drugs and other concomitantly prescribed drugs in hospitalized lung cancer patients. METHODS: A retrospective, observational, single-centre study was conducted on lung cancer inpatients from the medical records department of Kasturba Hospital, Manipal, India. Drug-drug interactions were identified using the drug interaction checkers of two drug information databases, Micromedex and Epocrates. These drug-drug interactions were categorized based on the source from which they were identified, mechanism, severity/significance, adverse consequences, and management strategies required. RESULTS: Among 196 patients, 555 drug-drug interactions were identified in 185 patients using Micromedex and Epocrates. Based on the mechanism of action, 74% and 22% of the drug-drug interactions were classified as pharmacodynamic and pharmacokinetic respectively. 112 drug-drug interactions were recorded from Micromedex alone, while 549 interactions were found using Epocrates. The oral chemotherapeutic drug gefitinib was found to be associated with the highest number of drug-drug interactions. CONCLUSION: Drug-drug interactions were highly prevalent among hospitalized lung cancer patients. Structured screening and monitoring for these potentially clinically relevant drug-drug interactions by oncologists in collaboration with clinical pharmacists should be carried out prior to initiation and during anticancer treatment to prevent adverse clinical outcomes.

Minor tropical fruits as a potential source of bioactive and functional foods.

Tropical fruits are defined as fruits that are grown in hot and humid regions within the Tropic of Cancer and Tropic of Capricorn, covering most of the tropical and subtropical areas of Asia, Africa, Central America, South America, the Caribbean and Oceania. Depending on the cultivation area covered, economic value and popularity these tropical fruits are divided into major and minor tropical fruits. There is an annual increment of 3.8% in terms of commercialization of the tropical fruits. In total 26 minor tropical fruits (Kiwifruit, Lutqua, Carambola, Tree Tomato, Elephant apple, Rambutan, Bay berry, Mangosteen, Bhawa, Loquat, Silver berry, Durian, Persimon, Longan, Passion fruit, Water apple, Pulasan, Indian gooseberry, Guava, Lychee, Annona, Pitaya, Sapodilla, Pepino, Jaboticaba, Jackfruit) have been covered in this work. The nutritional composition, phytochemical composition, health benefits, traditional use of these minor tropical fruits and their role in food fortification have been portrayed.

Chitosan based titanium and iron oxide hybrid bio-polymeric nanocomposites as potential corrosion inhibitor for mild steel in acidic medium.

Biopolymer chitosan (CS), chitosan grafted acrylamide based titanium dioxide (CS-g-PAM/TiO2) and magnetite (CS-g-PAM/Fe3O4) hybrid nanocomposites have been synthesized through free radical graft co-polymerization and successfully validated as corrosion inhibitors for mild steel in 15 % HCl solution. The synthesized compounds have been characterized through FTIR, APC, XRD and TEM. The thermal stability of the nanocomposites was established by TGA. The anticorrosive performance was determined through gravimetric measurements and by electrochemical study. According to EIS technique it was observed that CS-g-PAM/TiO2 and CS-g-PAM/Fe3O4 showed maximum 97.19 % and 95.49 % efficiency respectively. Langmuir adsorption isotherm is obeyed in each case. The activation and adsorption parameters have been determined from isotherm study. FESEM and AFM confirmed better adsorption layer formed by composites over mild steel surface. The elemental composition of the metal samples was proved by the XPS investigation. DFT and ANOVA test further corroborates the experimental results.

Polyphenolic Composition, Antioxidant, Antiproliferative and Antidiabetic Activities of Coronopus didymus Leaf Extracts.

Coronopus didymus (Brassicaceae) commonly known as lesser swine cress has been reported to be used for its pharmacological activities. This study aimed to evaluate the medicinal potential of C. didymus extracts against cancer, diabetes, infectious bacteria and oxidative stress and the identification of bioactive compounds present in these extracts. The effects of using different solvents for the extraction of C. didymus on the contents of major polyphenols and biological activities were investigated. Plant sample was shade dried, ground to a fine powder, and then soaked in pure acetone, ethanol and methanol. The highest contents of major polyphenols were found in methanol-based extract, i.e., chlorogenic acid, HB acid, kaempferol, ferulic acid, quercetin and benzoic acid with 305.02, 12.42, 11.5, 23.33, 975.7 and 428 mg/g of dry weight, respectively, followed by ethanol- and acetone-based extracts. The methanol-based extract also resulted in the highest antioxidant activities (56.76%), whereas the highest antiproliferative (76.36) and alpha glucosidase inhabitation (96.65) were demonstrated in ethanol-based extracts. No antibacterial property of C. didymus was observed against all the tested strains of bacteria. Further studies should be focused on the identification of specific bioactive compounds responsible for pharmacological activities.

An Evaluation of Antimicrobial, Anticancer, Anti-Inflammatory and Antioxidant Activities of Silver Nanoparticles Synthesized from Leaf Extract of Madhuca longifolia Utilizing Quantitative and Qualitative Methods.

In the current decade, nanoparticles are synthesized using solvents that are environmentally friendly. A number of nanoparticles have been synthesized at room temperature using water as a solvent, such as gold (Au) and silver (Ag) nanoparticles. As part of nanotechnology, nanoparticles are synthesized through biological processes. Biological methods are the preferred method for the synthesis of inorganic nanoparticles (AgNPs) as a result of their simple and non-hazardous nature. Nanoparticles of silver are used in a variety of applications, including catalysts, spectrally selective coatings for solar absorption, optical objectives, pharmaceutical constituents, and chemical and biological sensing. Antimicrobial agents are among the top uses of silver nanoparticles. In the current study, silver nanoparticles were biologically manufactured through Madhuca longifolia, and their antibacterial activity against pathogenic microorganisms, anticancer, anti-inflammatory, and antioxidant activities were assessed. UV-Vis spectroscopy, XRD (X-ray diffraction), transmission electron microscopy, Zeta Potential, and FTIR were used to characterize silver nanoparticles. The current work describes a cheap and environmentally friendly method to synthesize silver nanoparticles from silver nitrate solution by using plant crude extract as a reducing agent.

Green synthesis of metalloid nanoparticles and its biological applications: A review.

Synthesis of metalloid nanoparticles using biological-based fabrication has become an efficient alternative surpassing the existing physical and chemical approaches because there is a need for developing safer, more reliable, cleaner, and more eco-friendly methods for their preparation. Over the last few years, the biosynthesis of metalloid nanoparticles using biological materials has received increased attention due to its pharmaceutical, biomedical, and environmental applications. Biosynthesis using bacterial, fungal, and plant agents has appeared as a faster developing domain in bio-based nanotechnology globally along with other biological entities, thus posing as an option for conventional physical as well as chemical methods. These agents can efficiently produce environment-friendly nanoparticles with the desired composition, morphology (shape as well as size), and stability, along with homogeneity. Besides this, metalloid nanoparticles possess various applications like antibacterial by damaging bacterial cell membranes, anticancer due to damaging tumour sites, targeted drug delivery, drug testing, and diagnostic roles. This review summarizes the various studies associated with the biosynthesis of metalloid particles, namely, tellurium, arsenic, silicon, boron, and antimony, along with their therapeutic, pharmaceutical and environmental applications.

Cyclodextrin nanoparticles for diagnosis and potential cancer therapy: A systematic review.

Cancer is still one of the world's deadliest health concerns. As per latest statistics, lung, breast, liver, prostate, and cervical cancers are reported topmost worldwide. Although chemotherapy is most widely used methodology to treat cancer, poor pharmacokinetic parameters of anticancer drugs render them less effective. Novel nano-drug delivery systems have the caliber to improve the solubility and biocompatibility of various such chemical compounds. In this regard, cyclodextrins (CD), a group of natural nano-oligosaccharide possessing unique physicochemical characteristics has been highly exploited for drug delivery and other pharmaceutical purposes. Their cup-like structure and amphiphilic nature allows better accumulation of drugs, improved solubility, and stability, whereas CDs supramolecular chemical compatibility renders it to be highly receptive to various kinds of functionalization. Therefore combining physical, chemical, and bio-engineering approaches at nanoscale to specifically target the tumor cells can help in maximizing the tumor damage without harming non-malignant cells. Numerous combinations of CD nanocomposites were developed over the years, which employed photodynamic, photothermal therapy, chemotherapy, and hyperthermia methods, particularly targeting cancer cells. In this review, we discuss the vivid roles of cyclodextrin nanocomposites developed for the treatment and theranostics of most important cancers to highlight its clinical significance and potential as a medical tool.

Phenolic Constituents from Wendlandia tinctoria var. grandis (Roxb.) DC. Stem Deciphering Pharmacological Potentials against Oxidation, Hyperglycemia, and Diarrhea: Phyto-Pharmacological and Computational Approaches.

Wendlandia tinctoria var. grandis (Roxb.) DC. (Family: Rubiaceae) is a semi-evergreen shrub distributed over tropical and subtropical Asia. The present research intended to explore the pharmacological potential of the stem extract of W. tinctoria, focusing on the antioxidant, hypoglycemic, and antidiarrheal properties, and to isolate various secondary metabolites as mediators of such activities. A total of eight phenolic compounds were isolated from the dichloromethane soluble fraction of the stem extract of this plant, which were characterized by electrospray ionization (ESI) mass spectrometric and 1H NMR spectroscopic data as liquiritigenin (1), naringenin (2), apigenin (3), kaempferol (4), glabridin (5), ferulic acid (6), 4-hydroxybenzoic acid (7), and 4-hydroxybenzaldehyde (8). The dichloromethane soluble fraction exhibited the highest phenolic content (289.87 ± 0.47 mg of GAE/g of dried extract) and the highest scavenging activity (IC50 = 18.83 ± 0.07 µg/mL) against the DPPH free radical. All of the isolated compounds, except 4-hydroxybenzaldehyde, exerted a higher antioxidant effect (IC50 = 6.20 ± 0.10 to 16.11 ± 0.02 µg/mL) than the standard butylated hydroxytoluene (BHT) (IC50 = 17.09 ± 0.01 µg/mL). Significant hypoglycemic and antidiarrheal activities of the methanolic crude extract at both doses (200 mg/kg bw and 400 mg/kg bw) were observed in a time-dependent manner. Furthermore, the computational modeling study supported the current in vitro and in vivo findings, and the isolated constituents had a higher or comparable binding affinity for glutathione reductase and urase oxidase enzymes, glucose transporter 3 (GLUT 3), and kappa-opioid receptor, inferring potential antioxidant, hypoglycemic, and antidiarrheal properties, respectively. This is the first report of all of these phenolic compounds being isolated from this plant species and even the first demonstration of the plant stem extract's antioxidant, hypoglycemic, and antidiarrheal potentials. According to the current findings, the W. tinctoria stem could be a potential natural remedy for treating oxidative stress, hyperglycemia, and diarrhea. Nevertheless, further extensive investigation is crucial for thorough phytochemical screening and determining the precise mechanisms of action of the plant-derived bioactive metabolites against broad-spectrum molecular targets.

Central Composite Designed Fast Dissolving Tablets for Improved Solubility of the Loaded Drug Ondansetron Hydrochloride.

Ondansetron tablets that are directly compressed using crospovidone and croscarmellose as a synthetic super disintegrant are the subject of this investigation. A central composite, response surface, randomly quadratic, nonblock (version 13.0.9.0) 32 factorial design is used to optimize the formulation (two-factor three-level). To make things even more complicated, nine different formulation batches (designated as F1-F9) were created. There were three levels of crospovidone and croscarmellose (+1, 0, -1). In addition to that, pre- and postcompressional parameters were evaluated, and all evaluated parameters were found to be within acceptable range. Among all postcompressional parameter dispersion and disintegration time, in vitro drug release experiments (to quantify the amount of medication released from the tablet) and their percentage prediction error were shown to have a significant influence on three dependent variables. Various pre- and postcompression characteristics of each active component were tested in vitro. Bulk density, tap density, angle of repose, Carr's index, and the Hausner ratio were all included in this analysis, as were many others. This tablet's hardness and friability were also assessed along with its dimension and weight variations. Additional stability studies may be conducted using the best batch of the product. For this study, we utilised the Design-Expert software to select the formulation F6, which had dispersion times of 17.67 ± 0.03 seconds, disintegration times of 120.12 ± 0.55 seconds, and percentage drug release measurements of 99.25 ± 0.36 within 30 minutes. Predicted values and experimental data had a strong correlation. Fast dissolving pills of ondansetron hydrochloride may be created by compressing the tablets directly.

A Promising Review on Cyclodextrin Conjugated Paclitaxel Nanoparticles for Cancer Treatment.

This review presented the unique characteristics of different types of cyclodextrin polymers by non-covalent host-guest interactions to synthesize an inclusion complex. Various cancers are treated with different types of modified cyclodextrins, along with the anticancer drug paclitaxel. PTX acts as a mitotic inhibitor, but due to its low dissolution and permeability in aqueous solutions, it causes considerable challenges for drug delivery system (DDS) designs. To enhance the solubility, it is reformulated with derivatives of cyclodextrins using freeze-drying and co-solvent lyophilization methods. The present supramolecular assemblies involve cyclodextrin as a key mediator, which is encapsulated with paclitaxel and their controlled release at the targeted area is highlighted using different DDS. In addition, the application of cyclodextrins in cancer treatment, which reduces the off-target effects, is briefly demonstrated using various types of cancer cell lines. A new nano-formulation of PTX is used to improve the antitumor activity compared to normal PTX DDS in lungs and breast cancer is well defined in the present review.

Fucoxanthin: A Promising Phytochemical on Diverse Pharmacological Targets.

Fucoxanthin (FX) is a special carotenoid having an allenic bond in its structure. FX is extracted from a variety of algae and edible seaweeds. It has been proved to contain numerous health benefits and preventive effects against diseases like diabetes, obesity, liver cirrhosis, malignant cancer, etc. Thus, FX can be used as a potent source of both pharmacological and nutritional ingredient to prevent infectious diseases. In this review, we gathered the information regarding the current findings on antimicrobial, antioxidant, anti-inflammatory, skin protective, anti-obesity, antidiabetic, hepatoprotective, and other properties of FX including its bioavailability and stability characteristics. This review aims to assist further biochemical studies in order to develop further pharmaceutical assets and nutritional products in combination with FX and its various metabolites.

Flavonoids a Bioactive Compound from Medicinal Plants and Its Therapeutic Applications.

Plants generally secrete secondary metabolites in response to stress. These secondary metabolites are very useful for humankind as they possess a wide range of therapeutic activities. Secondary metabolites produced by plants include alkaloids, flavonoids, terpenoids, and steroids. Flavonoids are one of the classes of secondary metabolites of plants found mainly in edible plant parts such as fruits, vegetables, stems, grains, and bark. They are synthesized by the phenylpropanoid pathway. Flavonoids possess antibacterial, antiviral, antioxidant, anti-inflammatory, antimutagenic, and anticarcinogenic properties. Due to their various therapeutic applications, various pharmaceutical companies have exploited different plants for the production of flavonoids. To overcome this situation, various biotechnological strategies have been incorporated to improve the production of different types of flavonoids. In this review, we have highlighted the various types of flavonoids, their biosynthesis, properties, and different strategies to enhance the production of flavonoids.