Adjuvant Novel Nanocarrier-Based Targeted Therapy for Lung Cancer.

Lung cancer has the lowest survival rate due to its late-stage diagnosis, poor prognosis, and intra-tumoral heterogeneity. These factors decrease the effectiveness of treatment. They release chemokines and cytokines from the tumor microenvironment (TME). To improve the effectiveness of treatment, researchers emphasize personalized adjuvant therapies along with conventional ones. Targeted chemotherapeutic drug delivery systems and specific pathway-blocking agents using nanocarriers are a few of them. This study explored the nanocarrier roles and strategies to improve the treatment profile's effectiveness by striving for TME. A biofunctionalized nanocarrier stimulates biosystem interaction, cellular uptake, immune system escape, and vascular changes for penetration into the TME. Inorganic metal compounds scavenge reactive oxygen species (ROS) through their photothermal effect. Stroma, hypoxia, pH, and immunity-modulating agents conjugated or modified nanocarriers co-administered with pathway-blocking or condition-modulating agents can regulate extracellular matrix (ECM), Cancer-associated fibroblasts (CAF),Tyro3, Axl, and Mertk receptors (TAM) regulation, regulatory T-cell (Treg) inhibition, and myeloid-derived suppressor cells (MDSC) inhibition. Again, biomimetic conjugation or the surface modification of nanocarriers using ligands can enhance active targeting efficacy by bypassing the TME. A carrier system with biofunctionalized inorganic metal compounds and organic compound complex-loaded drugs is convenient for NSCLC-targeted therapy.

A correlation between oxidative stress and diabetic retinopathy: An updated review.

Oxidative stress (OS) is a cytopathic outcome of excessively generated reactive oxygen species (ROS), down regulated antioxidant defense signaling pathways, and the imbalance between the produced radicals and their clearance. It plays a role in the genesis of several illnesses, especially hyperglycemia and its effects. Diabetic retinal illness, a micro vascular side effect of the condition, is the prime reason of diabetic related blindness. The OS (directly or indirectly) is associated with diabetic retinopathy (DR) and related consequences. The OS is responsible to induce and interfere the metabolic signaling pathways to enhance influx of the polyol cascades and hexosamine pathways, stimulate Protein Kinase-C (PKC) variants, and accumulate advanced glycation end products (AGEs). Additionally, the inequity between the scavenging and generation of ROS is caused by the epigenetic alteration caused by hyperglycemia that suppresses the antioxidant defense system. Induced by an excessive buildup of ROS, retinal changes in structure and function include mitochondrial damage, cellular death, inflammation, and lipid peroxidation. Therefore, it is crucial to comprehend and clarify the mechanisms connected to oxidative stress that underlie the development of DR.

A Novel Quantum Dots-Based Fluorescent Sensor for Determination of the Anticancer Dacomitinib: Application to Dosage Forms.

One of the most promising drugs recently approved for the treatment of various types of cancer is dacomitinib, which belongs to the tyrosine kinase inhibitor class. The US Food and Drugs Administration (FDA) has recently approved dacomitinib as a first-line treatment for patients suffering from non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The current study proposes the design of a novel spectrofluorimetric method for determining dacomitinib based on newly synthesized nitrogen-doped carbon quantum dots (N-CQDs) as fluorescent probes. The proposed method is simple and does not require pretreatment or preliminary procedures. Since the studied drug does not have any fluorescent properties, the importance of the current study is magnified. When excited at 325 nm, N-CQDs exhibited native fluorescence at 417 nm, which was quantitatively and selectively quenched by the increasing concentrations of dacomitinib. The developed method involved the simple and green microwave-assisted synthesis of N-CQDs, using orange juice as a carbon source and urea as a nitrogen source. The characterization of the prepared quantum dots was performed using different spectroscopic and microscopic techniques. The synthesized dots had consistently spherical shapes and a narrow size distribution and demonstrated optimal characteristics, including a high stability and a high fluorescence quantum yield (25.3%). When assessing the effectiveness of the proposed method, several optimization factors were considered. The experiments demonstrated highly linear quenching behavior across the concentration range of 1.0-20.0 µg/mL with a correlation coefficient (r) of 0.999. The recovery percentages were found to be in the range of 98.50-100.83% and the corresponding relative standard deviation (%RSD) was 0.984. The proposed method was shown to be highly sensitive with a limit of detection (LOD) as low as 0.11 µg/mL. The type of mechanism by which quenching took place was also investigated by different means and was found to be static with a complementary inner filter effect. For quality purposes, the assessment of the validation criteria adhered to the ICHQ2(R1) recommendations. Finally, the proposed method was applied to a pharmaceutical dosage form of the drug (Vizimpro® Tablets) and the obtained results were satisfactory. Considering the eco-friendly aspect of the suggested methodology, using natural materials to synthesize N-CQDs and water as a diluting solvent added to its greenness profile.

Exploring Nanocarriers as Treatment Modalities for Skin Cancer.

Cancer is a progressive disease of multi-factorial origin that has risen worldwide, probably due to changes in lifestyle, food intake, and environmental changes as some of the reasons. Skin cancer can be classified into melanomas from melanocytes and nonmelanoma skin cancer (NMSC) from the epidermally-derived cell. Together it constitutes about 95% of skin cancer. Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) are creditworthy of 99% of NMSC due to the limited accessibility of conventional formulations in skin cancer cells of having multiple obstacles in treatment reply to this therapeutic regime. Despite this, it often encounters erratic bioavailability and absorption to the target. Nanoparticles developed through nanotechnology platforms could be the better topical skin cancer therapy option. To improve the topical delivery, the nano-sized delivery system is appropriate as it fuses with the cutaneous layer and fluidized membrane; thus, the deeper penetration of therapeutics could be possible to reach the target spot. This review briefly outlooks the various nanoparticle preparations, i.e., liposomes, niosomes, ethosomes, transferosomes, transethosomes, nanoemulsions, and nanoparticles technologies tested into skin cancer and impede their progress tend to concentrate in the skin layers. Nanocarriers have proved that they can considerably boost medication bioavailability, lowering the frequency of dosage and reducing the toxicity associated with high doses of the medication.

Effects of the Anthocyanin Hirsutidin on Gastric Ulcers: Improved Healing through Antioxidant Mechanisms.

The goal of this study was to determine the effect of hirsutidin on ethanol-induced stomach ulcers in rats. Rats (n = 24 rats/group) were separated at random into the following groups: normal saline-treated (normal control), ethanol-treated (ethanol control), 10 mg/kg hirsutidin + ethanol-treated (hirsutidin 10), and 20 mg/kg hirsutidin + ethanol-treated (hirsutidin 20). All the groups received the respective treatment orally for 7 days. On day 7, i.e., after 24 h of fasting, except for the normal control group, all the groups orally received 5 mL/kg of ethanol. Four hours later, rats were anaesthetized, serum was isolated from the blood, and biochemical tests were performed. The stomach tissue was utilized for ulcer grading, histology, and biochemical analysis. The rats developed stomach acidity and ulcers after being given ethanol based on increased ulcer score, disturbed cellular architecture, increased oxidative stress, myeloperoxidase and decreased endogenous antioxidants, and nitric oxide and prostaglandin E2 concentration. Ethanol-treated rats also displayed increased tumor necrosis factor-α, aspartate aminotransferase, alanine transaminase, alkaline phosphatase, and inflammatory cytokines. The treatment with hirsutidin protected and significantly restored all serum parameters in ethanol-induced stomach ulcers and may have antiulcer activity.

Peripheral mRNA Expression and Prognostic Significance of Emotional Stress Biomarkers in Metastatic Breast Cancer Patients.

Emotional stress is believed to be associated with increased tumor progression. Stress-induced epigenetic modifications can contribute to the severity of disease and poor prognosis in cancer patients. The current study aimed to investigate the expression profiles along with the prognostic significance of psychological stress-related genes in metastatic breast cancer patients, to rationalize the molecular link between emotional stress and cancer progression. We profiled the expression of selected stress-associated genes (5-HTT, NR3C1, OXTR, and FKBP5) in breast cancer including the stress evaluation of all participants using the Questionnaire on Distress in Cancer Patients-short form (QSC-R10). A survival database, the Kaplan-Meier Plotter, was used to explore the prognostic significance of these genes in breast cancer. Our results showed relatively low expressions of 5-HTT (p = 0.02) and OXTR (p = 0.0387) in metastatic breast cancer patients as compared to the non-metastatic group of patients. The expression of NR3C1 was low in tumor grade III as compared to grade II (p = 0.04). Additionally, the expression of NR3C1 was significantly higher in patients with positive estrogen receptor status. However, no significant difference was found regarding FKBP5 expression in breast cancer. The results suggest a potential implication of these genes in breast cancer pathology and prognosis.

mTOR as a Potential Target for the Treatment of Microbial Infections, Inflammatory Bowel Diseases, and Colorectal Cancer.

The mammalian target of rapamycin (mTOR) is the major controller of a number of important cellular activities, including protein synthesis, cell expansion, multiplication, autophagy, lysosomal function, and cellular metabolism. When mTOR interacts with specific adaptor proteins, it forms two complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTOR signaling system regulates gene transcription and protein manufacturing to control proliferation of cell, differentiation of immune cell, and tumor metabolism. Due to its vital role in case of microbial infections, inflammations and cancer development and progression, mTOR has been considered as a key therapeutic target for the development of targeted medication. As autophagy dysfunction is linked to changes in both innate and adaptive immune responses, bacterial clearance defects, and goblet and Paneth cell malfunction, all of these changes are linked to inflammatory bowel diseases (IBD) and colorectal cancer (CRC) pathogenesis. Preclinical and clinical data have shown that the inhibition and induction of autophagy have significant potential to be translated into the clinical applications. In IBD and several CRC models, mTORC1 inhibitors have been found effective. In the recent years, a number of novel mTOR inhibitors have been investigated in clinical trials, and a number of drugs have shown considerably enhanced efficacy when combined with mTOR inhibitors. The future developments in the mTOR targeting medications can benefit patients in individualized therapy. Advanced and innovative medicines that are more effective and have lower drug resistance are still in high demand. New findings could be relevant in medicine development, pharmacological modification, or future mTOR inhibitor research. Therefore, the goal of this review is to present a comprehensive account of current developments on the mTOR pathway and its inhibitors, with an emphasis on the management of microbial infections, the treatment of inflammatory bowel disease, and the management of colon cancer.

Green Tea Catechins Attenuate Neurodegenerative Diseases and Cognitive Deficits.

Neurodegenerative diseases exert an overwhelming socioeconomic burden all around the globe. They are mainly characterized by modified protein accumulation that might trigger various biological responses, including oxidative stress, inflammation, regulation of signaling pathways, and excitotoxicity. These disorders have been widely studied during the last decade in the hopes of developing symptom-oriented therapeutics. However, no definitive cure has yet been discovered. Tea is one of the world's most popular beverages. The same plant, Camellia Sinensis (L.).O. Kuntze, is used to make green, black, and oolong teas. Green tea has been most thoroughly studied because of its anti-cancer, anti-obesity, antidiabetic, anti-inflammatory, and neuroprotective properties. The beneficial effect of consumption of tea on neurodegenerative disorders has been reported in several human interventional and observational studies. The polyphenolic compounds found in green tea, known as catechins, have been demonstrated to have many therapeutic effects. They can help in preventing and, somehow, treating neurodegenerative diseases. Catechins show anti-inflammatory as well as antioxidant effects via blocking cytokines' excessive production and inflammatory pathways, as well as chelating metal ions and free radical scavenging. They may inhibit tau protein phosphorylation, amyloid beta aggregation, and release of apoptotic proteins. They can also lower alpha-synuclein levels and boost dopamine levels. All these factors have the potential to affect neurodegenerative disorders. This review will examine catechins' neuroprotective effects by highlighting their biological, pharmacological, antioxidant, and metal chelation abilities, with a focus on their ability to activate diverse cellular pathways in the brain. This review also points out the mechanisms of catechins in various neurodegenerative and cognitive diseases, including Alzheimer's, Parkinson's, multiple sclerosis, and cognitive deficit.

Potential Efficacy of ß-Amyrin Targeting Mycobacterial Universal Stress Protein by In Vitro and In Silico Approach.

The emergence of drug resistance and the limited number of approved antitubercular drugs prompted identification and development of new antitubercular compounds to cure Tuberculosis (TB). In this work, an attempt was made to identify potential natural compounds that target mycobacterial proteins. Three plant extracts (A. aspera, C. gigantea and C. procera) were investigated. The ethyl acetate fraction of the aerial part of A. aspera and the flower ash of C. gigantea were found to be effective against M. tuberculosis H37Rv. Furthermore, the GC-MS analysis of the plant fractions confirmed the presence of active compounds in the extracts. The Mycobacterium target proteins, i.e., available PDB dataset proteins and proteins classified in virulence, detoxification, and adaptation, were investigated. A total of ten target proteins were shortlisted for further study, identified as follows: BpoC, RipA, MazF4, RipD, TB15.3, VapC15, VapC20, VapC21, TB31.7, and MazF9. Molecular docking studies showed that ß-amyrin interacted with most of these proteins and its highest binding affinity was observed with Mycobacterium Rv1636 (TB15.3) protein. The stability of the protein-ligand complex was assessed by molecular dynamic simulation, which confirmed that ß-amyrin most firmly interacted with Rv1636 protein. Rv1636 is a universal stress protein, which regulates Mycobacterium growth in different stress conditions and, thus, targeting Rv1636 makes M. tuberculosis vulnerable to host-derived stress conditions.

Novel and Potential Small Molecule Scaffolds as DYRK1A Inhibitors by Integrated Molecular Docking-Based Virtual Screening and Dynamics Simulation Study.

The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a novel, promising and emerging biological target for therapeutic intervention in neurodegenerative diseases, especially in Alzheimer's disease (AD). The molMall database, comprising rare, diverse and unique compounds, was explored for molecular docking-based virtual screening against the DYRK1A protein, in order to find out potential inhibitors. Ligands exhibiting hydrogen bond interactions with key amino acid residues such as Ile165, Lys188 (catalytic), Glu239 (gk+1), Leu241 (gk+3), Ser242, Asn244, and Asp307, of the target protein, were considered potential ligands. Hydrogen bond interactions with Leu241 (gk+3) were considered key determinants for the selection. High scoring structures were also docked by Glide XP docking in the active sites of twelve DYRK1A related protein kinases, viz. DYRK1B, DYRK2, CDK5/p25, CK1, CLK1, CLK3, GSK3ß, MAPK2, MAPK10, PIM1, PKA, and PKCα, in order to find selective DYRK1A inhibitors. MM/GBSA binding free energies of selected ligand-protein complexes were also calculated in order to remove false positive hits. Physicochemical and pharmacokinetic properties of the selected six hit ligands were also computed and related with the proposed limits for orally active CNS drugs. The computational toxicity webserver ProTox-II was used to predict the toxicity profile of selected six hits (molmall IDs 9539, 11352, 15938, 19037, 21830 and 21878). The selected six docked ligand-protein systems were exposed to 100 ns molecular dynamics (MD) simulations to validate their mechanism of interactions and stability in the ATP pocket of human DYRK1A kinase. All six ligands were found to be stable in the ATP binding pocket of DYRK1A kinase.

Neuroprotective role of chrysin-loaded poly(lactic-co-glycolic acid) nanoparticle against kindling-induced epilepsy through Nrf2/ARE/HO-1 pathway.

Chrysin is the major bioactive compound of blue passionflower, an important medicinal plant used in traditional herbal formulations since ancient times. In the present study, we report that chrysin nanoparticles (chrysin NPs) protect Wistar rats against kindling-induced epilepsy. Nanoparticles of sizes less than 150 nm with a spherical shape were prepared using poly(d,l-lactic-co-glycolic acid) and polyvinyl alcohol, respectively, as polymer and stabilizer. Rats were injected with subconvulsive doses of pentylenetetrazole (PTZ) (35 mg/kg, intraperitoneal) every second day, with 22 injections in total, and on the same days, they received protective doses of the chrysin NPs (5 and 10 µg/mL, PO), respectively, 45 min before each PTZ injection. After the last PTZ injection, an average of thirteen seizure scores was recorded. Animals were killed by decapitation 24 h after a seizure. The cortex and hippocampus were removed and stored in liquid nitrogen for determining oxidative stress terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, histopathology, and reverse transcription-polymerase chain reaction for messenger RNA expression. The result showed chrysin NPs treatment has counteracted oxidative stress, reduced neuronal apoptosis, and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1. In conclusion, our findings demonstrate that the neuroprotective effect of chrysin NPs against kindling-induced epilepsy might be escorted by the alleviation of oxidative stress through the Nrf2/antioxidant response element/HO-1 pathway signal pathway.

Lipid Nanocapsule: A Novel Approach to Drug Delivery System Formulation Development.

Nanocapsules are polymeric nanoparticles encased in a polymeric coating composed of a predominantly non-ionic surfactant, macromolecules, phospholipids, and an oil core. Lipophilic drugs have been entrapped using various nanocarriers, including lipid cores, likely lipid nanocapsules, solid lipid nanoparticles, and others. A phase inversion temperature approach is used to create lipid nanocapsules. The PEG (polyethyleneglycol) is primarily utilised to produce nanocapsules and is a critical parameter influencing capsule residence time. With their broad drug-loading features, lipid nanocapsules have a distinct advantage in drug delivery systems, such as the capacity to encapsulate hydrophilic or lipophilic pharmaceuticals. Lipid nanocapsules, as detailed in this review, are surface modified, contain target-specific patterns, and have stable physical and chemical properties. Furthermore, lipid nanocapsules have target-specific delivery and are commonly employed as a marker in the diagnosis of numerous illnesses. This review focuses on nanocapsule synthesis, characterisation, and application, which will help understand the unique features of nanocapsules and their application in drug delivery systems.

Volatile Oil Containing Plants as Phytopharmaceuticals to Treat Psoriasis: A Review.

INTRODUCTION: Psoriasis is a chronic skin condition caused by an autoimmune response that accelerates the life cycle of skin cells, resulting in the characteristic symptoms of scaling, inflammation, and itching. METHODS: Palliative treatment options for psoriasis often prioritize the use of volatile oils. These oils contain monoterpenes, sesquiterpenes, and phenylpropanoids that are intricately linked to the molecular cascades involved in the pathogenesis and symptoms of psoriasis. To evaluate the antipsoriatic efficacy of volatile oils and their components, we conducted a systematic review of scientific studies. Our literature search encompassed various online databases, including PubMed, BIREME, SCIELO, Open Grey, Scopus, and ScienceDirect. The selected studies included experimental in vitro/in vivo assessments as well as clinical studies that examined the potential of volatile oils and their extracts as antipsoriatic agents. We excluded conference proceedings, case reports, editorials, and abstracts. Ultimately, we identified and evaluated a total of 12 studies for inclusion in our analysis. RESULTS: The data collected, compiled, and analyzed strongly support the interaction between volatile oils and their constituents with the key molecular pathways involved in the pathogenesis of psoriasis and the development of its symptoms. Volatile oils play a significant role in the palliative treatment of psoriasis, while their chemical constituents have the potential to reduce the symptoms and recurrence of this condition. CONCLUSION: The current review highlights that the constituents found in volatile oils offer distinct chemical frameworks that can be regarded as promising starting points for the exploration and development of innovative antipsoriatic agents.

From carcinogenesis to therapeutic avenues: lncRNAs and mTOR crosstalk in lung cancer.

Long non-coding RNAs (lncRNAs) have been demonstrated to have a crucial function in the modulation of the activity of genes, impacting a variety of homeostatic processes involving growth, survival, movement, and genomic consistency. Certain lncRNAs' aberrant expression has been linked to carcinogenesis, tumor growth, and therapeutic resistance. They are beneficial for the management of malignancies since they can function as cancer-causing or cancer-suppressing genes and behave as screening or prognosis indicators. The modulation of the tumor microenvironment, metabolic modification, and spread have all been linked to lncRNAs in lung cancer. Recent research has indicated that lncRNAs may interact with various mTOR signalling systems to control expression in lung cancer. Furthermore, the route can affect how lncRNAs are expressed. Emphasizing the function of lncRNAs as crucial participants in the mTOR pathway, the current review intends to examine the interactions between the mTOR cascade and the advancement of lung cancer. The article will shed light on the roles and processes of a few lncRNAs associated with the development of lung cancer, as well as their therapeutic prospects.

Non-coding RNAs: Key regulators of CDK and Wnt/ß-catenin signaling in cancer.

Non-coding RNAs (ncRNAs) have become important modulators of gene expression and biological processes, contributing significantly to the initiation and spread of cancer. This study focuses on the complex interactions between ncRNAs and two major signaling pathways-Wnt/ß-catenin signaling and cyclin-dependent kinase (CDK)-linked to cancer. We provide an overview of current research on the modulation of these pathways in many cancer types by distinct classes of ncRNAs, such as miRNAs, lncRNAs, and circRNAs. The review focuses on the processes by which ncRNAs regulate cancer cell survival, proliferation, and metastasis. These mechanical processes include CDK activity, the activation of the Wnt/ß-catenin cascade and cell cycle advancement. We also discuss the importance of ncRNAs in drug resistance and treatment outcomes, as well as prognosis markers (diagnostic) and therapeutic targets for cancer. Understanding these complex regulatory networks may help in a large way to improve cancer research and diagnosis - but also perhaps treat patients more effectively.

Targeting the p53-p21 axis in liver cancer: Linking cellular senescence to tumor suppression and progression.

Liver cancer is a major health epidemic worldwide, mainly due to its high mortality rates and limited treatment options. The association of cellular senescence to tumorigenesis and the cancer hallmarks remains a subject of interest in cancer biology. The p53-p21 signalling axis is an important regulator in restoring the cell's balance by supporting tumor suppression and tumorigenesis in liver cancer. We review the novel molecular mechanisms that p53 and its downstream effector, p21, employ to induce cellular senescence, making it last longer, and halt the proliferation of damaged hepatocytes to become tumorous cells. We also examine how dysregulation of this pathway contributes to HCC pathogenesis, proliferation, survival, acquired resistance to apoptosis, and increased invasiveness. Furthermore, we comprehensively describe the molecular cross-talk between the p53-p21 signalling axis and major cell cycle signalling pathways, including Wnt/ß-catenin, PI3K/Akt, and TGF-ß in liver cancer and provide an overview of promising candidates for chemoprevention and future therapeutic strategies. This review article explores the roles of the p53-p21 pathway in liver cancer, examining its function in promoting cellular senescence under normal conditions and its potential role in cancer progression. It also highlights novel therapeutic drugs and drug targets within the pathway and discusses the implications for treatment strategies and prognosis in liver cancer.

Therapeutic Potential of lncRNAs in Regulating Disulfidptosis for Cancer Treatment.

Non-coding RNAs (lncRNAs) play critical roles in various cellular processes, including a novel form of regulated cell death known as disulfidptosis, characterized by accumulating protein disulfide bonds and severe endoplasmic reticulum stress. This review highlights the therapeutic potential of lncRNAs in regulating disulfidptosis for cancer treatment, emphasizing their influence on key pathway components such as GPX4, SLC7A11, and PDIA family members. Recent studies have demonstrated that targeting specific lncRNAs can sensitize cancer cells to disulfidptosis, offering a promising approach to cancer therapy. The regulation of disulfidptosis by lncRNAs involves various signaling pathways, including oxidative stress, ER stress, and calcium signaling. This review also discusses the molecular mechanisms underlying lncRNA regulation of disulfidptosis, the challenges of developing lncRNA-based therapies, and the future potential of this rapidly advancing field in cancer research.

Green synthesized nitrogen-doped carbon quantum dots for the sensitive determination of larotrectinib in biological fluids and dosage forms: Evaluation of method greenness and selectivity.

Recently, the kinase receptor inhibitor drug larotrectinib has been approved as a monotherapy for the treatment of patients with solid tumors containing the neurotrophic receptor tyrosine kinase gene fusion. In this paper, a novel sensitive spectrofluorimetric method was proposed for the determination of larotrectinib based on nitrogen-doped carbon quantum dots (N-CQDs) fluorescent probes. The proposed method is the first spectroscopic method for analysis of the cited drug, which is simple to implement and involves no pre-treatment steps or complicated techniques. The N-CQDs synthesis was performed by adopting a straightforward, fast, and environmentally friendly approach. It was achieved by means of a standard domestic microwave with inexpensive and readily available starting materials: orange juice (carbon source) and urea (nitrogen source). The synthesized N-CQDs were subjected to microscopic and spectroscopic characterization procedures. They were found to be stable with a sufficiently high fluorescence quantum yield (25.3%) and a small particle size distribution (2-5 nm). The motivation for the use of N-CQDs in this study arose from their excellent fluorescence intensities at 417 nm when excited at 325 nm. Larotrectinib was found to have a quantitative and selective quenching effect on the QDs fluorescence allowing for its sensitive determination. The drug's quenching mechanism was investigated and found to be of the static type. Under optimal conditions, the proposed approach permitted the determination of larotrectinib over the concentration interval of 5.0-28.0 µg/mL. The method showed sufficient sensitivity with a detection limit of 0.19 µg/mL and a quantitation limit of 0.57 µg/mL, enabling the determination of LARO in spiked human plasma samples. The approach's recovery percentage was found to be in the range of 99.09-100.73% for pure samples and 97.35-102.59% for plasma samples. The study also successfully applied the proposed approach to the commercial oral solution form of larotrectinib (Vitrakvi®) with high selectivity. Method greenness was further evaluated by adopting two metric tools, including the complementary green analytical procedure index (ComplexGAPI) and Analytical GREENNESS metric approach (AGREE), and it was confirmed to be excellent green. The proposed method was validated in accordance with the ICHQ2 (R1) recommendations and is considered an excellent candidate for potential application in the therapeutic monitoring of larotrectinib.

Mechanistic of Vesicular Ethosomes and Elastic Liposomes on Permeation Profiles of Acyclovir across Artificial Membrane, Human Cultured EpiDerm, and Rat Skin: In Vitro-Ex Vivo Study.

Acyclovir (ACV) controls cutaneous herpes, genital herpes, herpes keratitis, varicella zoster, and chickenpox. From previously reported ACV formulations, we continued to explore the permeation behavior of the optimized ACV loaded optimized ethosome (ETHO2R) and elastic liposome (ELP3R) and their respective carbopol gels across artificial membrane, cultured human EpiDerm, and rat skin. Transepidermal water loss (TEWL), scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and atomic force microscopy (AFM) were used to investigate the mechanistic perspective of permeation behavior. The size values of reformulated ELP3-R and ETHO2-R were observed as 217 and 128 nm, respectively (close to previous report), whereas their respective gels showed as 231 and 252 nm, respectively. ETHO2R showed high elasticity, %EE, and low vesicle size. These were investigated for the diffusion rate of the drug permeation (3 h) across the artificial membrane, cultured human EpiDerm, and rat skin. ETHO2GR showed the highest permeation flux (78.42 µg/cm2/h), diffusion coefficient (8.24 × 10-5 cm2/h), and permeation coefficient (0.67 × 10-3 cm/h) of ACV across synthetic membrane, whereas diffusion coefficient (2.4 × 10-4 cm2/h) and permeation coefficient (0.8 × 10-3 cm/h) were maximum across EpiDerm for ETHO2GR. ETHO2R suspension showed maximized permeation flux (169.58 µg/cm2/h) and diffusion rate (0.293 mg/cm2/h1/2), suggesting the rapid internalization of vesicles with cultured skin cells at low viscosity. A similar observation was revealed using rat skin, wherein the permeation flux (182.42 µg/cm2/h), permeation coefficient (0.3 × 10-2 cm/h), and diffusion rate (0.315 mg/cm2/h1/2) of ETHO2R were relatively higher than ELP3R and ELP3GR. Relative small size (128 nm), low viscosity, ethanol-mediated ultra-deformability, high drug entrapment (98%), and elasticity (63.2) are associated with ETHO2R to provide remarkable permeation behavior across the three barriers. The value of TEWL for ETHO2R (21.9 g/m2h) was 3.71 times higher than untreated control (5.9 g/m2h), indicating ethanol-mediated maximized surficial skin lipid perturbation at 3 h of application, whereas the respective ETHO2GR-treated rat skin had TEWL value (18.6 g/m2h) slightly lower than ETHO2R due to gel-based hydration into the skin. SEL, CLSM, and AFM provided a mechanistic perspective of ETHO2R and ELP3R-mediated permeation across rat skin and carrier-mediated visualization (skin-vesicle interaction). AFM provided detailed nanoscale surface roughness topographical parameters of treated and untreated rat skin as supportive data to SEM and CLSM. Thus, ethosomes ETHO2R and respective gel assisted maximum permeation of ACV across rat skin and cultured human EpiDerm to control cutaneous herpes infection and herpes keratitis.

Determination of α1-acid glycoprotein (AGP) concentration by HPLC in patients following local infiltration analgesia for primary total hip arthroplasty and its relation to ropivacaine (total and unbound).

Introduction: This study was performed to determine the levels of α1-acid glycoprotein (AGP) in old-age patients undergoing total hip arthroplasty. AGP is considered an acute phase protein produced during the acute phase reaction in the body to various stimuli; their proper monitoring is thus important. Methods: In order to study how AGP concentrations in old age patients change in response to surgical stress (total hip arthroplasty), a high-performance liquid chromatography assay was performed to measure AGP levels. AGP was isolated from the plasma by adding perchloric acid and was analyzed using PLRP-S 4000°A column. The mobile phase consisted of 1 mL TFA/L of water (Solvent A pH 2) and 1 mL TFA/L of acetonitrile (Solvent B). The gradient used was as follows: 0 min 18% B and 82% A, 15 min 60% B and 40% A, and 17 min 60% B and 40% A followed by column re-equilibration for 7 min before the next injection. AGP peak was obtained between 8.8 and 8.9 min. The method was fully optimised according to established guidelines. Results: The data obtained were analyzed on ChromQuest software. AGP concentrations were determined in all samples, including baseline and samples taken at different timed intervals. The peak for AGP was obtained between 8.8 and 8.9 min for both standard AGP and patient plasma. The graphs indicate that AGP concentration in almost all patient samples increased considerably, especially after 4 h and 24 h-for example, initial concentration in patient 1 was 10.36 mg/100 mL but, after 24 h, increased to 23.50 mg/100 mL. There was thus almost a 13 mg/100 mL increase in 24 h, which is confirmed by AGP concentration increasing after various conditions, including surgery. The increased plasma protein binding was comparatively associated with the unchanged free fraction of the drug. Conclusion: This surgically induced increase in AGP concentration resulted in increased plasma protein binding of the drug (ropivacaine), which in turn kept the free portion of ropivacaine stable during the postoperative period.