Cyclic and Linear Peptides Containing Alternate WW and RR Residues as Molecular Cargo Delivery Tools.

Cell-impermeable and negatively charged compounds' cellular uptake across the cell membranes remains challenging. Herein, the synthesis of four linear [(WWRR)2, (WWRR)3, (WWRR)4, and (WWRR)5] and four cyclic ([WWRR]2, [WWRR]3, [WWRR]4, and [WWRR]5) peptides containing alternate two tryptophan (WW) and two arginine (RR) residues and their biological evaluation as molecular transporters are reported. The peptides did not show any significant cytotoxicity in different cell lines (MDA-MB-23, SK-OV-3, and HEK 293) at a concentration of 5 µM and after 3 h of incubation time. The uptake of fluorescence-labeled cargo molecules (F'-GpYEEI, F'-siRNA, and F'-3TC) in the presence of the peptides was monitored in different cell lines (SK-OV-3 and MDA-MB-231) with fluorescence-activated cell sorting. Among all the peptides, [WWRR]5 (C4) showed the highest cellular uptake of cargo molecules, indicating it can act as effective molecular transporter. Confocal microscopy in MDA-MB-231 cells showed the cellular uptake of F'-GpYEEI in the presence of C4 and the intracellular localization of fluorescence-labeled C4 (F'-C4) in the cytosol. The F'-C4 cellular uptake was found to be concentration- and time-dependent, as shown by flow cytometry in MDA-MB-231 cells. Confocal microscopy and flow cytometry of F'-C4 in MDA-MB-231 cells were examined alone and in the presence of different endocytosis inhibitors (chlorpromazine, methyl-ß-cyclodextrin, chloroquine, and nystatin). The data showed that the cellular uptake of F'-C4 in the presence of chlorpromazine, chloroquine, and methyl-ß-cyclodextrin was reduced but not completely eliminated, indicating that both energy-independent and energy-dependent pathways contributed to the cellular uptake of F'-C4. Similar results were obtained using the confocal microscopy of C4 and F'-GpYEEI in the presence of endocytosis inhibitors (chlorpromazine, methyl-ß-cyclodextrin, chloroquine, and nystatin). These data indicate that C4 has the potential to be used as a cell-penetrating peptide and cargo transporter.

Exploring LIPIDs for their potential to improves bioavailability of lipophilic drugs candidates: A review.

This review aims to provide a thorough examination of the benefits, challenges, and advancements in utilizing lipids for more effective drug delivery, ultimately contributing to the development of innovative approaches in pharmaceutical science. Lipophilic drugs, characterized by low aqueous solubility, present a formidable challenge in achieving effective delivery and absorption within the human body. To address this issue, one promising approach involves harnessing the potential of lipids. Lipids, in their diverse forms, serve as carriers, leveraging their unique capacity to enhance solubility, stability, and absorption of these challenging drugs. By facilitating improved intestinal solubility and selective lymphatic absorption of porously permeable drugs, lipids offer an array of possibilities for drug delivery. This versatile characteristic not only bolsters the pharmacological efficacy of drugs with low bioavailability but also contributes to enhanced therapeutic performance, ultimately reducing the required dose size and associated costs. This comprehensive review delves into the strategic formulation approaches that employ lipids as carriers to ameliorate drug solubility and bioavailability. Emphasis is placed on the critical considerations of lipid type, composition, and processing techniques when designing lipid-based formulations. This review meticulously examines the multifaceted challenges that come hand in hand with lipid-based formulations for lipophilic drugs, offering an insightful perspective on future trends. Regulatory considerations and the broad spectrum of potential applications are also thoughtfully discussed. In summary, this review presents a valuable repository of insights into the effective utilization of lipids as carriers, all aimed at elevating the bioavailability of lipophilic drugs.

Virosome: An engineered virus for vaccine delivery.

The purpose of immunization is the effective cellular and humoral immune response against antigens. Several studies on novel vaccine delivery approaches such as micro-particles, liposomes & nanoparticles, etc. against infectious diseases have been investigated so far. In contrast to the conventional approaches in vaccine development, a virosomes-based vaccine represents the next generation in the field of immunization because of its balance between efficacy and tolerability by virtue of its mechanism of immune instigation. The versatility of virosomes as a vaccine adjuvant, and delivery vehicle of molecules of different nature, such as peptides, nucleic acids, and proteins, as well as provide an insight into the prospect of drug targeting using virosomes. This article focuses on the basics of virosomes, structure, composition formulation and development, advantages, interplay with the immune system, current clinical status, different patents highlighting the applications of virosomes and their status, recent advances, and research associated with virosomes, the efficacy, safety, and tolerability of virosomes based vaccines and the future prospective.

Hybrid Cyclic-Linear Cell-Penetrating Peptides Containing Alternative Positively Charged and Hydrophobic Residues as Molecular Transporters.

The cell membrane properties create a significant obstacle in intracellular delivery of cell-impermeable and negatively charged molecules. Herein, we report the synthesis and biological evaluation of a novel series of hybrid cyclic-linear peptides containing alternative positive and hydrophobic amino acids on the ring and side chain [(RW)5]K(RW)X (X = 1-5) to compare their molecular transporter efficiency. The peptides were synthesized through Fmoc solid-phase peptide synthesis. In vitro cytotoxicity of the peptides showed that the peptides did not exhibit any significant cytotoxicity at the concentration of 10 µM in human leukemia carcinoma cell line (CCRF-CEM), human ovarian adenocarcinoma cells (SK-OV-3), human epithelial embryonic kidney healthy (HEK-293), and human epithelial mammary gland adenocarcinoma cells (MDA-MB-231) after 3 h incubation. The cellular uptake of a fluorescence-labeled phosphopeptide (F'-GpYEEI) and anti-human immunodeficiency virus (HIV) drugs (lamivudine (F'-3TC), emtricitabine (F'-FTC), Stavudine (F'-d4T)), where F' is carboxyfluorescein, was measured in the presence of the peptides in CCRF-CEM and SK-OV-3 cells. Among all peptides, [(RW)5K](RW)5 (10 µM) was the most efficient transporter that improved the cellular uptake of F'-GpYEEI (2 µM) by 18- and 11-fold in CCRF-CEM and SK-OV-3, respectively, compared with F'-GpYEEI alone. Fluorescence-activated cell sorting (FACS) analysis results indicated that the cellular uptake of fluorescence-labeled peptide (F'-[(RW)5K](RW)5) was only partially inhibited by chlorpromazine as an endocytosis inhibitor after 3 h incubation in MDA-MB-231 cells. These data suggest the potential of this series of hybrid cyclic-linear peptides as cell-penetrating peptides and molecular transporters.

Cyclic Peptides as Protein Kinase Inhibitors: Structure-Activity Relationship and Molecular Modeling.

Under-expression or overexpression of protein kinases has been shown to be associated with unregulated cell signal transduction in cancer cells. Therefore, there is major interest in designing protein kinase inhibitors as anticancer agents. We have previously reported [WR]5, a peptide containing alternative arginine (R) and tryptophan (W) residues as a non-competitive c-Src tyrosine kinase inhibitor. A number of larger cyclic peptides containing alternative hydrophobic and positively charged residues [WR]x (x = 6-9) and hybrid cyclic-linear peptides, [R6K]W6 and [R5K]W7, containing R and W residues were evaluated for their protein kinase inhibitory potency. Among all the peptides, cyclic peptide [WR]9 was found to be the most potent tyrosine kinase inhibitor. [WR]9 showed higher inhibitory activity (IC50 = 0.21 µM) than [WR]5, [WR]6, [WR]7, and [WR]8 with IC50 values of 0.81, 0.57, 0.35, and 0.33 µM, respectively, against c-Src kinase as determined by a radioactive assay using [γ-33P]ATP. Consistent with the result above, [WR]9 inhibited other protein kinases such as Abl kinase activity with an IC50 value of 0.35 µM, showing 2.2-fold higher inhibition than [WR]5 (IC50 = 0.79 µM). [WR]9 also inhibited PKCa kinase activity with an IC50 value of 2.86 µM, approximately threefold higher inhibition than [WR]5 (IC50 = 8.52 µM). A similar pattern was observed against Braf, c-Src, Cdk2/cyclin A1, and Lck. [WR]9 exhibited IC50 values of <0.25 µM against Akt1, Alk, and Btk. These data suggest that [WR]9 is consistently more potent than other cyclic peptides with a smaller ring size and hybrid cyclic-linear peptides [R6K]W6 and [R5K]W7 against selected protein kinases. Thus, the presence of R and W residues in the ring, ring size, and the number of amino acids in the structure of the cyclic peptide were found to be critical in protein kinase inhibitory potency. We identified three putative binding pockets through automated blind docking of cyclic peptides [WR](5-9). The most populated pocket is located between the SH2, SH3, and N-lobe domains on the opposite side of the ATP binding site. The second putative pocket is formed by the same domains and located on the ATP binding site side of the protein. Finally, a third pocket was identified between the SH2 and SH3 domains. These results are consistent with the non-competitive nature of the inhibition displayed by these molecules. Molecular dynamics simulations of the protein-peptide complexes indicate that the presence of either [WR]5 or [WR]9 affects the plasticity of the protein and in particular the volume of the ATP binding site pocket in different ways. These results suggest that the second pocket is most likely the site where these peptides bind and offer a plausible rationale for the increased affinity of [WR]9.

Design and Biological Evaluation of Colchicine-CD44-Targeted Peptide Conjugate in an In Vitro Model of Crystal Induced Inflammation.

Gout is an inflammatory arthritis due to the joint deposition of monosodium urate (MSU) crystals. Phagocytosis of MSU crystals by tissue macrophages results in the generation of reactive oxygen species (ROS) and production of inflammatory cytokines and chemokines. Colchicine use in gout is limited by severe toxicity. CD44 is a transmembrane glycoprotein that is highly expressed in tissue macrophages and may be involved in gout pathogenesis. The P6 peptide is a 20-amino acid residue peptide that binds to CD44. We hypothesized that the conjugation of colchicine to the P6 peptide would reduce its off-target cytotoxicity while preserving its anti-inflammatory effect. A modified version of P6 peptide and colchicine-P6 peptide conjugate were synthesized using Fmoc/tBu solid-phase and solution-phase chemistry, respectively. A glutaryl amide was used as a linker. The P6 peptide was evaluated for its binding to CD44, association, and internalization by macrophages. Cytotoxic effects of P6 peptide, colchicine, and colchicine-P6 peptide on macrophages were compared and the inhibition of ROS generation and interleukin-8 (IL-8) secretion in MSU-stimulated macrophages treated with P6 peptide, colchicine, or colchicine-P6 peptide was studied. We confirmed that the P6 peptide binds to CD44 and its association and internalization by macrophages were CD44-dependent. Colchicine (1, 10, and 25 µM) demonstrated a significant cytotoxic effect on macrophages while the P6 peptide and colchicine-P6 peptide conjugate (1, 10 and 25 µM) did not alter the viability of the macrophages. The P6 peptide (10 and 25 µM) reduced ROS generation and IL-8 secretion mediated by a reduction in MSU phagocytosis by macrophages. The colchicine-P6 peptide significantly reduced ROS generation and IL-8 secretion compared to the P6 peptide alone at 1 and 10 µM concentrations. Conjugation of colchicine to the P6 peptide reduced the cytotoxic effect of colchicine while preserving its anti-inflammatory activity.

Insights into the Effects of Ligand Binding on Leucyl-tRNA Synthetase Inhibitors for Tuberculosis: In Silico Analysis and Isothermal Titration Calorimetry Validation.

Incidences of drug-resistant tuberculosis have become common and are rising at an alarming rate. Aminoacyl t-RNA synthetase has been validated as a newer target against Mycobacterium tuberculosis. Leucyl t-RNA synthetase (LeuRS) is ubiquitously found in all organisms and regulates transcription, protein synthesis, mitochondrial RNA cleavage, and proofreading of matured t-RNA. Leucyl t-RNA synthetase promotes growth and development and is the key enzyme needed for biofilm formation in Mycobacterium. Inhibition of this enzyme could restrict the growth and development of the mycobacterial population. A database consisting of 2734 drug-like molecules was screened against leucyl t-RNA synthetase enzymes through virtual screening. Based on the docking scores and MMGBSA energy values, the top three compounds were selected for molecular dynamics simulation. The druggable nature of the top three hits was confirmed by predicting their pharmacokinetic parameters. The top three hits-compounds 1035 (ZINC000001543916), 1054 (ZINC000001554197), and 2077 (ZINC000008214483)-were evaluated for their binding affinity toward leucyl t-RNA synthetase by an isothermal titration calorimetry study. The inhibitory activity of these compounds was tested against antimycobacterial activity, biofilm formation, and LeuRS gene expression potential. Compound 1054 (Macimorelin) was found to be the most potent molecule, with better antimycobacterial activity, enzyme binding affinity, and significant inhibition of biofilm formation, as well as inhibition of the LeuRS gene expression. Compound 1054, the top hit compound, has the potential to be used as a lead to develop successful leucyl t-RNA synthetase inhibitors.

Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges.

The programmed death-1 receptor (PD-1) acts as a T-cell brake, and its interaction with ligand-1 (PD-L-1) interferes with signal transduction of the T-cell receptor. This leads to suppression of T-cell survival, proliferation, and activity in the tumor microenvironment resulting in compromised anticancer immunity. PD-1/PD-L-1 interaction blockade shown remarkable clinical success in various cancer immunotherapies. To date, most PD-1/PD-L-1 blockers approved for clinical use are monoclonal antibodies (mAbs); however, their therapeutic use are limited owing to poor clinical responses in a proportion of patients. mAbs also displayed low tumor penetration, steep production costs, and incidences of immune-related side effects. This strongly indicates the importance of developing novel inhibitors as cancer immunotherapeutic agents. Recently, advancements in the small molecule-based inhibitors (SMIs) that directly block the PD-1/PD-L-1 axis gained attention from the scientific community involved in cancer research. SMIs demonstrated certain advantages over mAbs, including longer half-lives, low cost, greater cell penetration, and possibility of oral administration. Currently, several SMIs are in development pipeline as potential therapeutics for cancer immunotherapy. To develop new SMIs, a wide range of structural scaffolds have been explored with excellent outcomes; biphenyl-based scaffolds are most studied. In this review, we analyzed the development of mAbs and SMIs targeting PD-1/PD-L-1 axis for cancer treatment. Altogether, the present review delves into the problems related to mAbs use and a detailed discussion on the development and current status of SMIs. This article may provide a comprehensive guide to medicinal chemists regarding the potential structural scaffolds required for PD-1/PD-L-1 interaction inhibition.

The emerging role of noncoding RNAs in the EGFR signaling pathway in lung cancer.

Noncoding ribonucleic acids (ncRNAs) have surfaced as essential orchestrators within the intricate system of neoplastic biology. Specifically, the epidermal growth factor receptor (EGFR) signalling cascade shows a central role in the etiological underpinnings of pulmonary carcinoma. Pulmonary malignancy persists as a preeminent contributor to worldwide mortality attributable to malignant neoplasms, with non-small cell lung carcinoma (NSCLC) emerging as the most predominant histopathological subcategory. EGFR is a key driver of NSCLC, and its dysregulation is frequently associated with tumorigenesis, metastasis, and resistance to therapy. Over the past decade, researchers have unveiled a complex network of ncRNAs, encompassing microRNAs, long noncoding RNAs, and circular RNAs, which intricately regulate EGFR signalling. MicroRNAs, as versatile post-transcriptional regulators, have been shown to target various components of the EGFR pathway, influencing cancer cell proliferation, migration, and apoptosis. Additionally, ncRNAs have emerged as critical modulators of EGFR signalling, with their potential to act as scaffolds, decoys, or guides for EGFR-related proteins. Circular RNAs, a relatively recent addition to the ncRNA family, have also been implicated in EGFR signalling regulation. The clinical implications of ncRNAs in EGFR-driven lung cancer are substantial. These molecules exhibit diagnostic potential as robust biomarkers for early cancer detection and personalized treatment. Furthermore, their predictive value extends to predicting disease progression and therapeutic outcomes. Targeting ncRNAs in the EGFR pathway represents a novel therapeutic approach with promising results in preclinical and early clinical studies. This review explores the increasing evidence supporting the significant role of ncRNAs in modulating EGFR signalling in lung cancer, shedding light on their potential diagnostic, prognostic, and therapeutic implications.

Bridging autoimmunity and epigenetics: The influence of lncRNA MALAT1.

Autoimmune disorders represent a heterogeneous spectrum of conditions defined by an immune system's atypical reactivity against endogenous constituents. In the complex anatomy of autoimmune pathogenesis, lncRNAs have appeared as pivotal arbiters orchestrating the mechanisms of ailment initiation, immune cascades, and transcriptional modulation. One such lncRNA, MALAT1, has garnered attention for its potential association with the aetiology of several autoimmune diseases. MALAT1 has been shown to influence a wide spectrum of cellular processes, which include cell multiplication and specialization, as well as apoptosis and inflammation. In autoimmune diseases, MALAT1 exhibits both disease-specific and shared patterns of dysregulation, often correlating with disease severity. The molecular mechanisms underlying MALAT1's impact on autoimmune disorders include epigenetic modifications, alternative splicing, and modulation of gene expression networks. Additionally, MALAT1's intricate interactions with microRNAs, other lncRNAs, and protein-coding genes further underscore its role in immune regulation and autoimmune disease progression. Understanding the contribution of MALAT1 in autoimmune pathogenesis across different diseases could offer valuable insights into shared pathways, thereby clearing a path for the creation of innovative and enhanced therapeutic approaches to address these complex disorders. This review aims to elucidate the complex role of MALAT1 in autoimmune disorders, encompassing rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), type 1 diabetes, systemic lupus erythematosus, and psoriasis. Furthermore, it discusses the potential of MALAT1 as a diagnostic biomarker, therapeutic target, and prognostic indicator.

From inflammation to metastasis: The central role of miR-155 in modulating NF-κB in cancer.

Cancer is a multifaceted, complex disease characterized by unchecked cell growth, genetic mutations, and dysregulated signalling pathways. These factors eventually cause evasion of apoptosis, sustained angiogenesis, tissue invasion, and metastasis, which makes it difficult for targeted therapeutic interventions to be effective. MicroRNAs (miRNAs) are essential gene expression regulators linked to several biological processes, including cancer and inflammation. The NF-κB signalling pathway, a critical regulator of inflammatory reactions and oncogenesis, has identified miR-155 as a significant participant in its modulation. An intricate network of transcription factors known as the NF-κB pathway regulates the expression of genes related to inflammation, cell survival, and immunological responses. The NF-κB pathway's dysregulation contributes to many cancer types' development, progression, and therapeutic resistance. In numerous cancer models, the well-studied miRNA miR-155 has been identified as a crucial regulator of NF-κB signalling. The p65 subunit and regulatory molecules like IκB are among the primary targets that miR-155 directly targets to alter NF-κB activity. The molecular processes by which miR-155 affects the NF-κB pathway are discussed in this paper. It also emphasizes the miR-155's direct and indirect interactions with important NF-κB cascade elements to control the expression of NF-κB subunits. We also investigate how miR-155 affects NF-κB downstream effectors in cancer, including inflammatory cytokines and anti-apoptotic proteins.

Phytoimmunomodulators: A review of natural modulators for complex immune system.

In the past few decades, the medicinal properties of plants and their effects on the human immune system are being studied extensively. Plants are an incredible source of traditional medicines that help cure various diseases, including altered immune mechanisms and are economical and benign compared to allopathic medicines. Reported data in written documents such as Traditional Chinese medicine, Indian Ayurvedic medicine support the supplementation of botanicals for immune defense reactions in the body and can lead to safe and effective immunity responses. Additionally, some botanicals are well-identified as magical herbal remedies because they act upon the pathogen directly and help boost the immunity of the host. Chemical compounds, also known as phytochemicals, obtained from these botanicals looked promising due to their effects on the human immune system by modulating the lymphocytes which subsequently reduce the chances of getting infected. This paper summarises most documented phytochemicals and how they act on the immune system, their properties and possible mechanisms, screening conventions, formulation guidelines, comparison with synthetic immunity-enhancers, marketed immunity-boosting products, and immune-booster role in the ongoing ghastly corona virus wave. However, it focuses mainly on plant metabolites as immunomodulators. In addition, it also sheds light on the current advancements and future possibilities in this field. From this thorough study, it can be stated that the plant-based secondary metabolites contribute significantly to immunity building and could prove to be valuable medicaments for the design and development of novel immunomodulators even for a pandemic like COVID-19.

Precision arrows: Navigating breast cancer with nanotechnology siRNA.

Nanotechnology-based drug delivery systems, including siRNA, present an innovative approach to treating breast cancer, which disproportionately affects women. These systems enable personalized and targeted therapies, adept at managing drug resistance and minimizing off-target effects. This review delves into the current landscape of nanotechnology-derived siRNA transport systems for breast cancer treatment, discussing their mechanisms of action, preclinical and clinical research, therapeutic applications, challenges, and future prospects. Emphasis is placed on the importance of targeted delivery and precise gene silencing in improving therapeutic efficacy and patient outcomes. The review addresses specific hurdles such as specificity, biodistribution, immunological reactions, and regulatory approval, offering potential solutions and avenues for future research. SiRNA drug delivery systems hold promise in revolutionizing cancer care and improving patient outcomes, but realizing their full potential necessitates ongoing research, innovation, and collaboration. Understanding the intricacies of siRNA delivery mechanisms is pivotal for designing effective cancer treatments, overcoming challenges, and advancing siRNA-based therapies for various diseases, including cancer. The article provides a comprehensive review of the methods involved in siRNA transport for therapeutic applications, particularly in cancer treatment, elucidating the complex journey of siRNA molecules from extracellular space to intracellular targets. Key mechanisms such as endocytosis, receptor-mediated uptake, and membrane fusion are explored, alongside innovative delivery vehicles and technologies that enhance siRNA delivery efficiency. Moreover, the article discusses challenges and opportunities in the field, including issues related to specificity, biodistribution, immune response, and clinical translation. By comprehending the mechanisms of siRNA delivery, researchers can design and develop more effective siRNA-based therapies for various diseases, including cancer.

Computational insights into KRAS G12C inhibition: exploring possible repurposing of Azacitidine and Ribavirin.

Kirsten rat sarcoma (KRAS) stands out as the most prevalent mutated oncogene, playing a crucial role in the initiation and progression of various cancer types, including colorectal, lung and pancreatic cancer. The oncogenic modifications of KRAS are intricately linked to tumor development and are identified in 22% of cancer patients. This has spurred the necessity to explore inhibition mechanisms, with the aim of investigating and repurposing existing drugs for diagnosing cancers dependent on KRAS G12C In this investigation, 26 nucleoside-based drugs were collected from literature to assess their effectiveness against KRAS G12C. The study incorporates in-silico molecular simulations and molecular docking examinations of these nucleoside-derived drugs with the KRAS G12C protein using Protein Data Bank (PDB) ID: 5V71. The docking outcomes indicated that two drugs, Azacitidine and Ribavirin, exhibited substantial binding affinities of -8.7 and -8.3 kcal/mol, respectively. These drugs demonstrated stability in binding to the active site of the protein during simulation studies. Root mean square deviation (RMSD) analyses indicated that the complexes closely adhered to an equilibrium RMSD value ranging from 0.17 to 0.2 nm. Additionally, % occupancies, bond angles and the length of hydrogen bonds were calculated. These findings suggest that Azacitidine and Ribavirin may potentially serve as candidates for repurposing in individuals with KRAS-dependent cancers.Communicated by Ramaswamy H. Sarma.

Unveiling the potential of proteomic and genetic signatures for precision therapeutics in lung cancer management.

Lung cancer's enduring global significance necessitates ongoing advancements in diagnostics and therapeutics. Recent spotlight on proteomic and genetic biomarker research offers a promising avenue for understanding lung cancer biology and guiding treatments. This review elucidates genetic and proteomic lung cancer biomarker progress and their treatment implications. Technological strides in mass spectrometry-based proteomics and next-generation sequencing enable pinpointing of genetic abnormalities and abnormal protein expressions, furnishing vital data for precise diagnosis, patient classification, and customized treatments. Biomarker-driven personalized medicine yields substantial treatment improvements, elevating survival rates and minimizing adverse effects. Integrating omics data (genomics, proteomics, etc.) enhances understanding of lung cancer's intricate biological milieu, identifying novel treatment targets and biomarkers, fostering precision medicine. Liquid biopsies, non-invasive tools for real-time treatment monitoring and early resistance detection, gain popularity, promising enhanced management and personalized therapy. Despite advancements, biomarker repeatability and validation challenges persist, necessitating interdisciplinary efforts and large-scale clinical trials. Integrating artificial intelligence and machine learning aids analyzing vast omics datasets and predicting treatment responses. Single-cell omics reveal cellular connections and intratumoral heterogeneity, valuable for combination treatments. Biomarkers enable accurate diagnosis, tailored medicines, and treatment response tracking, significantly impacting personalized lung cancer care. This approach spurs patient-centered trials, empowering active patient engagement. Lung cancer proteomic and genetic biomarkers illuminate disease biology and treatment prospects. Progressing towards individualized efficient therapies is imminent, alleviating lung cancer's burden through ongoing research, omics integration, and technological strides.

Integrating network pharmacology with molecular docking to rationalize the ethnomedicinal use of Alchornea laxiflora (Benth.) Pax & K. Hoffm. for efficient treatment of depression.

Background: Alchornea laxiflora (Benth.) Pax & K. Hoffm. (A. laxiflora) has been indicated in traditional medicine to treat depression. However, scientific rationalization is still lacking. Hence, this study aimed to investigate the antidepressant potential of A. laxiflora using network pharmacology and molecular docking analysis. Materials and methods: The active compounds and potential targets of A. laxiflora and depression-related targets were retrieved from public databases, such as PubMed, PubChem, DisGeNET, GeneCards, OMIM, SwissTargetprediction, BindingDB, STRING, and DAVID. Essential bioactive compounds, potential targets, and signaling pathways were predicted using in silico analysis, including BA-TAR, PPI, BA-TAR-PATH network construction, and GO and KEGG pathway enrichment analysis. Later on, with molecular docking analysis, the interaction of essential bioactive compounds of A. laxiflora and predicted core targets of depression were verified. Results: The network pharmacology approach identified 15 active compounds, a total of 219 compound-related targets, and 14,574 depression-related targets with 200 intersecting targets between them. SRC, EGFR, PIK3R1, AKT1, and MAPK1 were the core targets, whereas 3-acetyloleanolic acid and 3-acetylursolic acid were the most active compounds of A. laxiflora with anti-depressant potential. GO functional enrichment analysis revealed 129 GO terms, including 82 biological processes, 14 cellular components, and 34 molecular function terms. KEGG pathway enrichment analysis yielded significantly enriched 108 signaling pathways. Out of them, PI3K-Akt and MAPK signaling pathways might have a key role in treating depression. Molecular docking analysis results exhibited that core targets of depression, such as SRC, EGFR, PIK3R1, AKT1, and MAPK1, bind stably with the analyzed bioactive compounds of A. laxiflora. Conclusion: The present study elucidates the bioactive compounds, potential targets, and pertinent mechanism of action of A. laxiflora in treating depression. A. laxiflora might exert an antidepressant effect by regulating PI3K-Akt and MAPK signaling pathways. However, further investigations are required to validate.

A comprehensive overview of selective and novel fibroblast growth factor receptor inhibitors as a potential anticancer modality.

The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment. Fibroblast growth factor receptor (FGFR) gene alterations are frequent findings in various rare and advanced cancers refractive to mainstay chemo-therapy or surgical interventions. Several FGFR inhibitors have been developed for addressing these genetically altered FGFR-harboring malignancies, and some have performed well in clinical trials. In contrast, others are still being investigated in different phases of clinical trials. FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. These include cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid malignancies. Pemigatinib is the only FGFR inhibitor globally approved (USA, EU, and Japan) and available as a targeted therapy for two types of cancer, including FGFR2 fusion or other rearrangements harboring cholangiocarcinoma and relapsed/refractory myeloid/lymphoid neoplasms with FGFR1 rearrangements. Myeloid/lymphoid neoplasm is the latest area of application added to the therapeutic armamentarium of FGFR inhibitors. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.

Amphiphilic Cell-Penetrating Peptides Containing Arginine and Hydrophobic Residues as Protein Delivery Agents.

The entry of proteins through the cell membrane is challenging, thus limiting their use as potential therapeutics. Seven cell-penetrating peptides, designed in our laboratory, were evaluated for the delivery of proteins. Fmoc solid-phase peptide synthesis was utilized for the synthesis of seven cyclic or hybrid cyclic-linear amphiphilic peptides composed of hydrophobic (tryptophan (W) or 3,3-diphenylalanine (Dip) and positively-charged arginine (R) residues, such as [WR]4, [WR]9, [WWRR]4, [WWRR]5, [(RW)5K](RW)5, [R5K]W7, and [DipR]5. Confocal microscopy was used to screen the peptides as a protein delivery system of model cargo proteins, green and red fluorescein proteins (GFP and RFP). Based on the confocal microscopy results, [WR]9 and [DipR]5 were found to be more efficient among all the peptides and were selected for further studies. [WR]9 (1-10 µM) + protein (GFP and RFP) physical mixture did not show high cytotoxicity (>90% viability) in triple-negative breast cancer cells (MDA-MB-231) after 24 h, while [DipR]5 (1-10 µM) physical mixture with GFP exhibited more than 81% cell viability. Confocal microscopy images revealed internalization of GFP and RFP in MDA-MB-231 cells using [WR]9 (2-10 µM) and [DipR]5 (1-10 µM). Fluorescence-activated cell sorting (FACS) analysis indicated that the cellular uptake of GFP was concentration-dependent in the presence of [WR]9 in MDA-MB-231 cells after 3 h of incubation at 37 °C. The concentration-dependent uptake of GFP and RFP was also observed in the presence of [DipR5] in SK-OV-3 and MDA-MB-231 cells after 3 h of incubation at 37 °C. FACS analysis indicated that the cellular uptake of GFP in the presence of [WR]9 was partially decreased by methyl-ß-cyclodextrin and nystatin as endocytosis inhibitors after 3 h of incubation in MDA-MB-231 cells, whereas nystatin and chlorpromazine as endocytosis inhibitors slightly reduced the uptake of GFP in the presence of [DipR]5 after 3 h of incubation in MDA-MB-231. [WR]9 was able to deliver therapeutically relevant proteins (Histone H2A) at different concentrations. These results provide insight into the use of amphiphilic cyclic peptides in the delivery of protein-related therapeutics.

Molecular Chaperones as Therapeutic Target: Hallmark of Neurodegenerative Disorders.

Misfolded and aggregated proteins build up in neurodegenerative illnesses, which causes neuronal dysfunction and ultimately neuronal death. In the last few years, there has been a significant upsurge in the level of interest towards the function of molecular chaperones in the control of misfolding and aggregation. The crucial molecular chaperones implicated in neurodegenerative illnesses are covered in this review article, along with a variety of their different methods of action. By aiding in protein folding, avoiding misfolding, and enabling protein breakdown, molecular chaperones serve critical roles in preserving protein homeostasis. By aiding in protein folding, avoiding misfolding, and enabling protein breakdown, molecular chaperones have integral roles in preserving regulation of protein balance. It has been demonstrated that aging, a significant risk factor for neurological disorders, affects how molecular chaperones function. The aggregation of misfolded proteins and the development of neurodegeneration may be facilitated by the aging-related reduction in chaperone activity. Molecular chaperones have also been linked to the pathophysiology of several instances of neuron withering illnesses, enumerating as Parkinson's disease, Huntington's disease, and Alzheimer's disease. Molecular chaperones have become potential therapy targets concerning with the prevention and therapeutic approach for brain disorders due to their crucial function in protein homeostasis and their connection to neurodegenerative illnesses. Protein homeostasis can be restored, and illness progression can be slowed down by methods that increase chaperone function or modify their expression. This review emphasizes the importance of molecular chaperones in the context of neuron withering disorders and their potential as therapeutic targets for brain disorders.

Improved Photocatalytic and Antioxidant Activity of Olive Fruit Extract-Mediated ZnO Nanoparticles.

Photodegradation is an efficient strategy for the removal of organic pollutants from wastewater. Due to their distinct properties and extensive applications, semiconductor nanoparticles have emerged as promising photocatalysts. In this work, olive (Olea Europeae) fruit extract-based zinc oxide nanoparticles (ZnO@OFE NPs) were successfully biosynthesized using a one-pot sustainable method. The prepared ZnO NPs were systematically characterized using UV-Vis, FTIR, SEM, EDX and XRD and their photocatalytic and antioxidant activity was evaluated. SEM demonstrated the formation of spheroidal nanostructures (57 nm) of ZnO@OFE and the EDX analysis confirmed its composition. FTIR suggested the modification/capping of the NPs with functional groups of phytochemicals from the extract. The sharp XRD reflections revealed the crystalline nature of the pure ZnO NPs with the most stable hexagonal wurtzite phase. The photocatalytic activity of the synthesized catalysts was evaluated by measuring the degradation of methylene blue (MB) and methyl orange (MO) dyes under sunlight irradiation. Improved degradation efficiencies of 75% and 87% were achieved within only 180 min with photodegradation rate constant k of 0.008 and 0.013 min-1 for MB and MO, respectively. The mechanism of degradation was proposed. Additionally, ZnO@OFE NPs exhibited potent antioxidant activity against DPPH, hydroxyl, peroxide and superoxide radicals. Hence, ZnO@OFE NPs may have potential as a cost-effective and green photocatalyst for wastewater treatment.