Search

Chemotherapy is a key treatment option for gastric cancer, but over 50% of patients develop either inherent or acquired resistance to these drugs, resulting in a 5-year survival rate of only about 20%. The primary treatment for advanced gastric cancer typically involves chemotherapy based on platinum or fluorouracil. Several factors can contribute to platinum resistance, including decreased drug uptake, increased drug efflux or metabolism, enhanced DNA repair, activation of pro-survival pathways, and inhibition of pro-apoptotic pathways. In recent years, there has been significant progress in biology aimed at finding innovative and more effective methods to overcome chemotherapy resistance. Small interfering RNAs (siRNAs) have emerged as a significant advancement in gene expression regulation, showing promise in enhancing the sensitivity of gastric cancer cells to chemotherapy drugs. However, siRNA therapies still face major challenges, particularly in terms of stability and efficient delivery in vivo. This article discusses the advances in siRNA therapy and its potential role in overcoming resistance to chemotherapeutic drugs such as cisplatin, 5-FU, doxorubicin, and paclitaxel in the treatment of gastric cancer., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

MicroRNAs (miRNAs) are conserved non-protein-coding RNAs that are naturally present in organisms and can control gene expression by suppressing the translation of mRNA or causing the degradation of mRNA. MicroRNAs are highly concentrated in the PI3K/AKT pathway, and abnormal activation of the PI3K/AKT pathway plays a role in cancer progression. The AKT/PI3K pathway is critical for cellular functions and can be stimulated by cytokines and in normal situations. It is involved in regulating various intracellular signal transduction, including development, differentiation, transcriptional regulation, protein, and synthesis. There is a growing body of evidence indicating that miRNAs, which are abundant in exosomes released by different cells, can control cellular biological activities via modulating the PI3K/AKT pathway, hence influencing cancer progression and drug resistance. This article provides an overview of the latest research progress regarding the function and medical use of the PI3K/AKT pathway and exosomal miRNA/AKT/PI3K axis in the behaviors of cancer cells., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Istamycins (ISMs) are 2-deoxyfortamine-containing aminoglycoside antibiotics (AGAs) produced by Streptomyces tenjimariensis ATCC 31603 with broad-spectrum bactericidal activities against most of the clinically relevant pathogens. Therefore, this study aimed to statistically optimize the environmental conditions affecting ISMs production using the central composite design (CCD). Both the effect of culture media composition and incubation time and agitation rate were studied as one factor at the time (OFAT). The results showed that both the aminoglycoside production medium and the protoplast regeneration medium gave the highest specific productivity. Results also showed that 6 days incubation time and 200 rpm agitation were optimum for their production. A CCD quadratic model of 17 runs was employed to test three key variables: initial pH, incubation temperature, and concentration of calcium carbonate. A significant statistical model was obtained including, an initial pH of 6.38, incubation temperature of 30 ˚C, and 5.3% CaCO 3 concentration. This model was verified experimentally in the lab and resulted in a 31-fold increase as compared to the unoptimized conditions and a threefold increase to that generated by using the optimized culture media. To our knowledge, this is the first report about studying environmental conditions affecting ISM production as OFAT and through CCD design of the response surface methodology (RSM) employed for statistical optimization. In conclusion, the CCD design is an effective tool for optimizing ISMs at the shake flask level. However, the optimized conditions generated using the CCD model in this study should be scaled up in a fermenter for industrial production of ISMs by S. tenjimariensis ATCC 31603 considering the studied environmental conditions that significantly influence the production proces., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Chimeric Antigen Receptor (CAR) based therapies are becoming increasingly important in treating patients. CAR-T cells have been shown to be highly effective in the treatment of hematological malignancies. However, harmful therapeutic barriers have been identified, such as the potential for graft-versus-host disease (GVHD), neurotoxicity, and cytokine release syndrome (CRS). As a result, CAR NK-cell therapy is expected to be a new therapeutic option. NK cells act as cytotoxic lymphocytes, supporting the innate immune response against autoimmune diseases and cancer cells by precisely detecting and eliminating malignant cells. Genetic modification of these cells provides a dual approach to the treatment of AD and cancer. It can be used through both CAR-independent and CAR-dependent mechanisms. The use of CAR-based cell therapies has been successful in treating cancer patients, leading to further investigation of this innovative treatment for alternative diseases, including AD. The complementary roles of CAR T and CAR NK cells have stimulated exploration in this area. Our study examines the latest research on the therapeutic effectiveness of these cells in treating both cancer and ADs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Staphylococcus sciuri (also currently Mammaliicoccus sciuri) are anaerobic facultative and non-motile bacteria that cause significant human pathogenesis such as endocarditis, wound infections, peritonitis, UTI, and septic shock. Methicillin-resistant S. sciuri (MRSS) strains also infects animals that include healthy broilers, cattle, dogs, and pigs. The emergence of MRSS strains thereby poses a serious health threat and thrives the scientific community towards novel treatment options. Herein, we investigated the druggable genome of S. sciuri by employing subtractive genomics that resulted in seven genes/proteins where only three of them were predicted as final targets. Further mining the literature showed that the ArgS (WP&#95;058610923), SecY (WP&#95;058611897), and MurA (WP&#95;058612677) are involved in the multi-drug resistance phenomenon. After constructing and verifying the 3D protein homology models, a screening process was carried out using a library of Traditional Chinese Medicine compounds (consisting of 36,043 compounds). The molecular docking and simulation studies revealed the physicochemical stability parameters of the docked TCM inhibitors in the druggable cavities of each protein target by identifying their druggability potential and maximum hydrogen bonding interactions. The simulated receptor-ligand complexes showed the conformational changes and stability index of the secondary structure elements. The root mean square deviation (RMSD) graph showed fluctuations due to structural changes in the helix-coil-helix and beta-turn-beta changes at specific points where the pattern of the RMSD and root mean square fluctuation (RMSF) (< 1.0 Å) support any major domain shifts within the structural framework of the protein-ligand complex and placement of ligand was well complemented within the binding site. The β-factor values demonstrated instability at few points while the radius of gyration for structural compactness as a time function for the 100-ns simulation of protein-ligand complexes showed favorable average values and denoted the stability of all complexes. It is assumed that such findings might facilitate researchers to robustly discover and develop effective therapeutics against S. sciuri alongside other enteric infections., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acute myeloid leukemia (AML) is characterized by disruption of intracellular signaling due to aberration of extracellular signaling pathways, namely PI3K/AKT cascade, by dysregulating erythropoiesis and myelopoiesis. Therefore, inhibition of PI3K/AKT, either individually, or by dual inhibitors, is shown to be effective in suppression of tumorigenesis. To increase the therapeutic viability and decrease adverse effects, including cytotoxicity due to off-target kinase inhibitions, customized targeted pharmacological agents are needed that would have greater treatment potential. In this work, using an interdisciplinary approach, we have identified dual inhibitors targeted to PI3K and AKT to significantly repress the cell proliferation in AML cancers. Diversity-based high-throughput virtual screening (D-HTVS) technique followed by conventional docking approach identified small molecules from ChemBridge library, having high binding affinity for PI3KCG subunit. Further computational screening of top identified PI3K-specific lead molecules predicts dual inhibitors with high binding affinity for AKT. To rule out the possibility for cross-reaction/off-target effects of identified small molecules, lead compounds having nil or negligible binding to PI3KCA- and PI3KCB subunits were chosen. Computational screening, enzyme inhibition and cell proliferation assays show compound C16,5-{[(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)amino]methylene}-1-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione has better affinity for PI3KCG, delta, and AKT kinases compared to their respective known/established inhibitors, and has significant anti-cell proliferation activity in AML cells with a GI 50 values of 77.25 nM and 49.65 nM in THP-1 and HL-60 cells, respectively. This work proposes a novel dual inhibitor that selectively targets PI3K/AKT and suppresses cell proliferation in AML cells as a potential lead molecule for treating AML cancers., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)