Inhibition Of DNA Synthesis Research Articles

In Silico Study of the Potential Inhibitory Effects on Escherichia coli DNA Gyrase of Some Hypothetical Fluoroquinolone–Tetracycline Hybrids

Background/Objectives: Despite the discovery of antibiotics, bacterial infections persist globally, exacerbated by rising antimicrobial resistance that results in millions of cases, increased healthcare costs, and more extended hospital stays. The urgent need for new antibacterial drugs continues as resistance evolves. Fluoroquinolones and tetracyclines are versatile antibiotics that are effective against various bacterial infections. A hybrid antibiotic combines two or more molecules to enhance antimicrobial effectiveness and combat resistance better than monotherapy. Fluoroquinolones are ideal candidates for hybridization due to their potent bactericidal effects, ease of synthesis, and ability to form combinations with other molecules. Methods: This study explored the mechanisms of action for 40 hypothetical fluoroquinolone–tetracycline hybrids, all of which could be obtained using a simple, eco-friendly synthesis method. Their interaction with Escherichia coli DNA Gyrase and similarity to albicidin were evaluated using the FORECASTER platform. Results: Hybrids such as Do-Ba, Mi-Fi, and Te-Ba closely resembled albicidin in physicochemical properties and FITTED Scores, while Te-De surpassed it with a better score. Similar to fluoroquinolones, these hybrids likely inhibit DNA synthesis by binding to enzyme–DNA complexes. Conclusions: These hybrids could offer broad-spectrum activity and help mitigate bacterial resistance, though further in vitro and in vivo studies are needed to validate their potential.

Cuproptosis-related lncRNAs emerge as a novel signature for predicting prognosis in prostate carcinoma and functional experimental validation.

Prostate cancer (PCa) is one of the most common malignancies of the urinary system. Cuproptosis, a newly discovered form of cell death. The relationship between cuproptosis-related long non-coding RNAs (ClncRNAs) related to PCa and prognosis remains unclear. This study aimed to explore the clinical significance of novel ClncRNAs in the prognostic assessment of PCa. ClncRNAs and differentially expressed mRNAs linked to these ClncRNAs were identified using Pearson's correlation and differential expression analyses. A prognostic signature (risk score) comprising three ClncRNAs was established based on multivariable Cox regression analysis. The predictive performance of this ClncRNAs signature was validated using receiver operating characteristic curves and nomograms. Finally, further in vitro cell experiments were conducted for validation, including quantitative polymerase chain reaction (qPCR), western blot (WB), cell proliferation assays, cell migration assays, cell invasion assays, apoptosis, and cell cycle analysis. We constructed a prognostic signature of ClncRNAs for PCa comprising three key differentially expressed ClncRNAs(AC010896-1, AC016394-2, and SNHG9). Multivariable Cox regression analysis indicated that clinical staging and risk scores of the ClncRNAs signature were independent prognostic factors for PCa. Compared to other clinical features, the ClncRNAs signature exhibited higher diagnostic efficiency and performed well in predicting the 1-, 3-, and 5-year progression-free intervals (PFIs) for PCa. Notably, in terms of immune activity, PCa patients with high-risk scores exhibited higher tumor mutational burden (TMB) levels, while their Tumor Immune Dysfunction and Exclusion (TIDE) scores were lower than those of PCa patients with low-risk scores. Additionally, in vitro cellular functional experiments, we knocked down SNHG9 that is the most significantly differentially expressed ClncRNA among the three key ClncRNAs. SNHG9 knockdown resulted in a significant increase in G1 phase cells and a decrease in S and G2 phases, indicating inhibition of DNA synthesis and cell cycle progression. Colony formation assays showed reduced clonogenic ability, with fewer and smaller colonies. Western blot analysis revealed the upregulation of the key cuproptosis-related mRNAs FDX1 and DLST. These findings suggested that SNHG9 promotes PCa cell proliferation, migration, and invasion. Building on the three ClncRNAs, we identified a novel prognostic signature of PCa. The ClncRNA SNHG9 can promote PCa cell proliferation, migration, and invasion.

Enhancing antibacterial efficacy through macrocyclic host complexation of fluoroquinolone antibiotics for overcoming resistance

The use of supramolecular assemblies in pharmaceuticals has garnered significant interest. Recent studies have shown that the activities of antibacterial agents can be enhanced through complexation with cyclic oligomers and metal ions. Notably, these complexes sometimes possess greater therapeutic properties than the parent drugs. To develop microbiologically potent supramolecular drugs, the complexation of macrocyclic hosts with fluoroquinolone (FQ) antibiotics was investigated. FQs are a successful family of antibiotics that target the bacterial enzymes DNA gyrase and DNA topoisomerase IV, leading to bacterial cell death through the inhibition of DNA synthesis. However, antibiotic resistance resulting from the repeated use of FQs over time has limited their effectiveness against resistant pathogens. To overcome this issue, the encapsulation of FQs in polyphenolic macrocycles was investigated. This study highlights resorcinarene, a polyphenolic host with antibacterial properties, and its ability to chemically interact with FQs. The inclusion complexation process was analyzed using NMR and FTIR techniques. The binding constants determined by 1H-NMR titration revealed that levofloxacin forms more stable complexes with resorcinarene than with β-cyclodextrin, which aligned with MD simulations. Assessment of the geometric characteristics of the inclusion complexes using 2D NMR analysis confirmed that different moieties of various FQs can fit into a single host cavity and improve activity against gram-negative bacteria. Overall, these findings suggest that encapsulation in polyphenolic macrocycles is a promising strategy for utilizing FQs against antibiotic-resistant bacteria.

Maribavir use in pediatric immunocompromised hosts: A case series to talk about real-world experience

Abstract Background Cytomegalovirus (CMV) is a common infection affecting pediatric immunocompromised hosts. The treatment of CMV in solid organ (SOT) or hematopoietic stem cell transplant (HSCT) patients is challenged by the toxicities associated with antiviral therapies (myelosuppression with valganciclovir, ganciclovir and cidofovir; nephrotoxicity with foscarnet and cidofovir) and the prevalence of resistant/refractory CMV. Maribavir, a novel benzimidazole, competitively inhibits CMV UL97 protein kinase to inhibit DNA synthesis and block nuclear exit of viral particles from CMV-infected cells. It is FDA approved for use in patients at least 12 years of age and weighing at least 35 kg. The use of maribavir in pediatric patients is of interest due to its availability as an oral dosage formulation and improved side effect profile. To date, there are no pediatric case series or studies describing the use of maribavir for CMV treatment. Methods This study is a retrospective case series compiling the findings the first pediatric patients at Children’s National Hospital, DC that received maribavir. We included children who received maribavir from 01/2017 – 10/2023. Patients were included if they were on maribavir monotherapy, or combination therapy with additional anti-CMV agent(s). The medical records were reviewed for indication of medication use, viral response to therapy and side effects. Side-effects review specifically evaluated for increased LFTs, increased serum creatinine, and decreased absolute neutrophil count or factors that may contribute to early discontinuation of maribavir. Results (table) Maribavir was used in three male patients with varied conditions – including solid organ transplant (SOT), hematopoietic stem cell transplant (HSCT) and Severe Combined Immunodeficiency (SCID) s/p HSCT. Two cases had signs of CMV disease, and one had CMV viremia. All cases included documented CMV resistance (n=2) or refractory CMV (n=1) and had previously been receiving at least one antiviral with CMV activity for at least 14 days and had increasing CMV DNA-emia in the blood. None of the patients had side effects such as nephrotoxicity, liver toxicity or myelosuppression that aggravated after starting maribavir. Dosing of 400mg BID (range 12mg/kg/day to 55mg/kg/day) was used. Once started, maribavir was continued until CMV quantitative levels were undetectable for two weeks. Clearance of CMV and was achieved in all the patients on maribavir or combination of maribavir with other drugs (n=1). Duration of maribavir treatment ranged from 4.2 to 6.2 weeks. Conclusion This is the first case series describing use of maribavir in a pediatric population. In this small cohort maribavir is effective and well tolerated. Further studies are needed to better CMV care in children with immunocompromised conditions.

The Antibacterial Efficacy and Mechanism of Tea Polyphenol Against Drug-Resistant Aeromonas veronii TH0426 In Vitro.

The emergence of Motile Aeromonas Septicemia (MAS) caused by Aeromonas veronii in sturgeon farming has become a significant concern due to its high mortality impact on the aquaculture industry. The threat posed by MAS highlights the urgent need for effective control measures to combat bacterial infections in sturgeon populations. Tea polyphenol (TP) has demonstrated promising antibacterial properties against livestock and poultry bacterial infections. However, its antibacterial efficacy and mechanism in bacterial diseases of aquatic animals remain largely unexplored. This study aimed to investigate the in vitro antibacterial effect and mechanism of TP on fish-borne drug-resistant A. veronii TH0426 by assessing the impact of TP on TH0426 cell growth, antibiofilm activity, morphology, as well as measuring electrical conductivity, DNA extravasation, lactate dehydrogenase (LDH) activity, protein, and DNA contents. Results demonstrated that the minimum inhibitory concentration and the minimum bactericidal concentration of TP on TH0426 were 1024 and 2048 μg/mL, respectively. After a 4 h treatment, the growth of TH0426 was completely inhibited at the concentration of 1024 and 2048 μg/mL of TP. Meanwhile, TP exhibited a significant antibiofilm activity. Both scanning electron microscope and transmission electron microscope analyses revealed disrupted cell membrane structure, irregular cell morphology, and loss of intracellular contents following TP treatment. Moreover, increased cell membrane permeability induced by TP led to intracellular ion and DNA leakage, resulting in elevated electrical conductivity and DNA extravasation. Furthermore, TP decreased LDH activity, protein concentration and content, DNA fluorescence intensity, and density in a time-dependent manner, indicating inhibition of protein metabolism and DNA synthesis. In conclusion, TP exhibits potent antibacterial properties by inhibiting biofilm formation, disrupting cell membrane integrity, and interfering with protein metabolism and DNA synthesis in drug-resistant A. veronii TH0426 in vitro.

Immune-related and common adverse events with PD-1/PD-L1 inhibitors combined with other anticancer therapy for solid tumors: a systematic review and meta-analysis

AimsThe combination of programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) inhibitors and anticancer therapies has been in the spotlight in recent years. However, the risks associated with these combination therapies are not fully elucidated. The primary objective of this study was to evaluate the relative risk of organ-specific immune-related adverse events (irAEs) and common adverse events (AEs) in patients treated with PD-1/PD-L1 inhibitor-based combination therapies compared to those treated with PD-1/PD-L1 inhibitor monotherapy for solid tumors. Materials and methodsAn electronic database search was performed using ClinicalTrials.gov, Medline, and ASCO/ESMO Annual Meeting Libraries. We included randomized controlled trials designed to assess the safety of combination therapies using PD-1/PD-L1 inhibitors and other anticancer drugs. All the selected clinical studies included solid tumors and provided information on the incidence of non-serious and serious AEs. The quality of evidence was assessed using the Cochrane risk-of-bias tool. A meta-analysis was performed using random effects models to pool the results. ResultsThe primary analysis included 16 relevant clinical studies comprising 4232 patients, of whom 2071 and 2161 patients received PD-1/PD-L1 inhibitor-based combination therapy, and PD-1/PD-L1 inhibitor monotherapy, respectively. Serious organ-specific irAEs were infrequent, even when PD-1/PD-L1 inhibitors were combined with other anticancer drugs. The incidence of serious colitis was significantly higher in the combination therapy group than in the monotherapy group. Among the common AEs associated with PD-1/PD-L1 inhibitors, the incidence of serious pyrexia/fever, non-serious pyrexia/fever, fatigue, nausea, decreased appetite, vomiting, diarrhea, dyspnea, and rash significantly increased in the combination therapy group. In the subgroup analysis based on the modes of action of concomitant anticancer drugs, the combination of PD-1/PD-L1 inhibitors and DNA synthesis inhibitors significantly increased the risk of serious colitis compared to PD-1/PD-L1 inhibitor monotherapy. ConclusionOrgan-specific irAEs occur infrequently when combinations of PD-1/PD-L1 inhibitors and other anticancer drugs are used. However, the risk of serious colitis and certain AEs is higher than that associated with PD-1/PD-L1 inhibitor monotherapy. Vigilant monitoring of AEs and implementation of appropriate clinical management strategies guided by the mode of action of the combination drugs are essential. ProsperoRegistration number CRD42022379088.

Function of Moringa oleifera Lamk Leaf Extract as an Antiseptic for Pseudomonas aeruginosa and Staphylococcus aureus using Percentage Kill Method

Moringa oleifera Lamk leaf extract has an antimicrobial properties especially against fungal, parasite, Gram positive and negative bacteria by inhibiting DNA synthesis and metabolism an damaging cell walls. The aim of this study was to determine whether M. oleifera Lamk leaf extract is effective as an antiseptic against P. aeruginosa and S. aureus bacteria. Percentage Kill was used in the study to determine the percentage of bacteria death after contact with M. oleifera Lamk leaf extract in the 1st, 2nd and 5th minutes against the control and treatment simultaneously. The test is considered to meet the standard if each contact gives a result of ≥90%. For discovered percentage kill to P. aeruginosa bacteria in the 1st, 2nd and 5th minutes each test showed a yield of 27.12%. , 47.01%, 57.7%. In the third time of P. aeruginosa did not reach the standard. Whereas in S. aureus bacteria, each test showed a yield of 92.36%, 95.58% and 96.45%, where it was seen that all results reach the standards criteria of ≥90%. M. oleifera Lamk leaf extract was not effective in eliminating P. aeruginosa for all contacts because the standard value was below 90%. Whereas for S. aureus bacteria, M. oleifera Lamk leaf extract was very effective in eliminating bacteria for all contact times ≥90% with the highest value at the 5th minutes (96.45%).

L-Glutamine mitigates bile acid-induced inhibition of growth factor activity in rat hepatocyte cultures

Bile acid-induced hepatotoxicity is inevitable in Cholestasis pathogenesis and L-Glutamine (L-Gln) has been reported to prevent total parenteral nutrition (TPN)-induced cholestasis in premature neonates. While mechanisms remain unknown, we hypothesize that bile acids impair growth factor (GF) function in hepatocytes which L-glutamine prevents through NAPDH oxidase (NOX) modulation. Glycochenodeoxycholic acid (GCDC, 0–100 µM) when added to primary hepatocyte cultures significantly (p < 0.01) decreased the FBS-induced BrdU incorporation, however inhibition of Fibroblast Growth factor (FGF)- or Hepatocyte growth factor (HGF)-induced DNA synthesis was more pronounced (p < 0.001). L-Gln markedly attenuated GCDC-mediated inhibition of DNA synthesis in both FBS and GF-treated cells. GCDC significantly increased the NADPH oxidase activity and NOX-1 protein expression that were markedly reduced by L-Gln and protein kinase c (PKC) inhibitor, LY-333531. Apocynin (APCN) and diphenyliodonium (DPI) significantly blocked the GCDC-mediated inhibition of GF-induced DNA synthesis. This study demonstrates that bile acid-induced hepatotoxicity involves dysfunction of certain growth factors via protein kinase c (PKC)- mediated NOX modulation which can be corrected, at least partly, by L-glutamine.

Synthesis, Characterization, and In vitro and In Silico Studies of New Triazole Derivatives as Aromatase Inhibitors

Introduction: Breast cancer is the most common type of cancer among women. Steroidal or non-steroidal aromatase inhibitors (NSAIs) are used clinically, and in most cancer diseases, resistance is the most important problem. Method: The nitrogenous heterocyclic ring is noteworthy in the structure of non-steroidal aromatase inhibitors. This is the pharmacophore structure for aromatase inhibition. Because the enzyme interacts with the Fe2+ cation of the HEM structure in its active site, the most used agents in the clinic, such as anastrozole and letrozole, contain triazoles in their structures. Within the scope of this study, hybrid compounds containing both imidazole and triazole were synthesized. Result: The synthesis was carried out by a 4-step reaction. The anticancer effects of the compounds were evaluated by MTT assay performed on A549 and MCF-7 cancer cells. Compound 4d showed anticancer activity against the MCF-7 cell line with IC50=6.7342 uM value. This compound exhibited anticancer activity against the A549 cell line with an IC50 = 17.1761 μM. In the MTT test performed on a healthy cell line to determine the cytotoxic effects of the compounds, the compound showed activity with a value of 4d IC50=13.2088 uM. This indicates that the compound is not cytotoxic. Additionally, BrdU analysis was performed to evaluate whether the compound inhibits DNA synthesis. These selective effects of the compounds on breast cancer strengthened their aromatase enzyme inhibitor potential. For this reason, experiments conducted with both in vitro and in silico methods revealed a compound with high aromatase inhibitor potential. Conclusion: The interactions observed as a result of molecular docking and dynamics studies are in harmony with activity studies. In particular, interactions with HEM600 demonstrate the activity potential of the compound.

Nsp1 stalls DNA Polymerase α at DNA hairpins.

The human primosome, a four-subunit complex of DNA primase and DNA polymerase alpha (Polα), plays a critical role in DNA replication by initiating RNA and DNA synthesis on both chromosome strands. A recent study has shown that a major virulence factor in the SARS-CoV-2 infection, Nsp1 (non-structural protein 1), forms a stable complex with Polα but does not affect the primosome activity. Here we show that Nsp1 inhibits DNA synthesis across inverted repeats prone to hairpin formation. Analysis of current structural data revealed the overlapping binding sites for Nsp1 and the winged helix-turn-helix domain of RPA (wHTH) on Polα, indicating a competition between them. Comparison of the inhibitory effect of Nsp1 and wHTH on DNA hairpin bypass by Polα showed an 8-fold lower IC 50 value for Nsp1 (1 µM). This study provides a valuable insight into the mechanism of inhibition of human DNA replication by Nsp1 during a SARS-CoV-2 infection.

Cytotoxic Activity of Novel GnRH Analogs Conjugated with Mitoxantrone in Ovarian Cancer Cells.

The gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) is highly expressed in ovarian cancer cells (OCC), and it is an important molecular target for cancer therapeutics. To develop a new class of drugs targeting OCC, we designed and synthesized Con-3 and Con-7 which are novel high-affinity GnRH-R agonists, covalently coupled through a disulfide bond to the DNA synthesis inhibitor mitoxantrone. We hypothesized that Con-3 and Con-7 binding to the GnRH-R of OCC would expose the conjugated mitoxantrone to the cellular thioredoxin, which reduces the disulfide bond of Con-3 and Con-7. The subsequent release of mitoxantrone leads to its intracellular accumulation, thus exerting its cytotoxic effects. To test this hypothesis, we determined the cytotoxic effects of Con-3 and Con-7 using the SKOV-3 human OCC. Treatment with Con-3 and Con-7, but not with their unconjugated GnRH counterparts, resulted in the accumulation of mitoxantrone within the SKOV-3 cells, increased their apoptosis, and reduced their proliferation, in a dose- and time-dependent manner, with half-maximal inhibitory concentrations of 0.6-0.9 µM. It is concluded that Con-3 and Con-7 act as cytotoxic "prodrugs" in which mitoxantrone is delivered in a GnRH-R-specific manner and constitute a new class of lead compounds for use as anticancer drugs targeting ovarian tumors.

Bioflavonoid Baicalein Modulates Tetracycline Resistance by Inhibiting Efflux Pump in Staphylococcus aureus.

The rise in antibiotic resistance among bacterial pathogens, particularly Staphylococcus aureus, has become a critical global health issue, necessitating the search for novel antimicrobial agents. S. aureus uses various mechanisms to resist antibiotics, including the activation of efflux pumps, biofilm formation, and enzymatic modification of drugs. This study explores the potential of baicalein, a bioflavonoid from Scutellaria baicalensis, in modulating tetracycline resistance in S. aureus by inhibiting efflux pumps. The synergistic action of baicalein and tetracycline was evaluated through various assays. The minimum inhibitory concentration (MIC) of baicalein and tetracycline against S. aureus was 256 and 1.0 μg/mL, respectively. Baicalein at 64 μg/mL reduced the MIC of tetracycline by eightfold, indicating a synergistic effect (fractional inhibitory concentration index: 0.375). Time-kill kinetics demonstrated a 1.0 log CFU/mL reduction in bacterial count after 24 hours with the combination treatment. The ethidium bromide accumulation assay showed that baicalein mediated significant inhibition of efflux pumps, with a dose-dependent increase in fluorescence. In addition, baicalein inhibited DNA synthesis by 73% alone and 92% in combination with tetracycline. It also markedly reduced biofilm formation and the invasiveness of S. aureus into HeLa cells by 52% at 64 μg/mL. These findings suggest that baicalein enhances tetracycline efficacy and could be a promising adjunct therapy to combat multidrug-resistant S. aureus infections.

Anticancer Plant Secondary Metabolites Induce Linker Histone Depletion from Chromatin.

Many plant secondary metabolites (PSMs) were shown to intercalate into DNA helix or interact with DNA grooves. This may influence histone-DNA interactions changeing chromatin structure and genome functioning. Nucleosome stability and linker histone H1.2, H1.4 and H1.5 localizations were studied in HeLa cells after the treatment with 15 PSMs, which are DNA-binders and possess anticancer activity according to published data. Chromatin remodeler CBL0137 was used as a control. Effects of PSMs were studied using fluorescent microscopy, flowcytometry, quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR), western-blotting. We showed that 1-hour treatment with CBL0137 strongly inhibited DNA synthesis and caused intensive linker histone depletion consistent with nucleosome destabilization. None of PSMs caused nucleosome destabilization, while most of them demonstrated significant influence on linker histone localizations. In particular, cell treatment with 11 PSMs at non-toxic concentrations induced significant translocation of the histone H1.5 to nucleoli and most of PSMs caused depletion of the histones H1.2 and H1.4 from chromatin fraction. Curcumin, resveratrol, berberine, naringenin, and quercetin caused significant redistribution of all three variants of the studied linker histones showing some overlap of PSM effects on linker histone DNA-binding. We demonstrated that PSMs, which induced the most significant redistribution of the histone H1.5 (berberine, curcumin and naringenin), influence the proportion of cells synthesizing DNA, expressing or non-expressing cyclin B and influence cell cycle distribution. Berberine induction of H1.5 translocations to nucleoli was shown to occur independently on the phases of cell cycle (metaphase was not analyzed). For the first time we revealed PSM influence on linker histone location in cell nuclei that opens a new direction of PSM research as anticancer agents.

Near-infrared-responsive Prussian blue nanocages loaded with 5-fluorouracil for combined chemotherapy and photothermal therapy in tumor treatment.

Nanodrug delivery systems (NDDS) have been proposed to improve the targeting and bioavailability of chemotherapy drugs. The approach of drug loading via physical adsorption is facile to operate; however, there exists a risk of premature leakage. Coupling the drug molecules with the carrier through chemical reactions can guarantee the stability of the drug delivery process, yet the preparation procedure is relatively intricate. In this research, a kind of Prussian blue nanocage (PB Cage) was fabricated, and the phase change material, 1-pentadecanol, was used as the gating material to solidify 5-fluorouracil (5-FU) inside the nanocage. Upon irradiation with near-infrared (NIR) light, the temperature of the PB Cage can rise rapidly. When the temperature exceeds 43 °C, 1-pentadecanol undergoes a solid-liquid phase transition and subsequently releases 5-FU to inhibit DNA synthesis. Meanwhile, the photothermal therapy (PTT) mediated by the PB Cage is also capable of ablating tumor cells. The NDDS constructed based on PB has achieved the precise release of 5-FU triggered by NIR light, which may avoid side effects on normal tissues. Moreover, the combination of chemotherapy and photothermal therapy can efficaciously suppress the proliferation of tumor cells.

Comparative analysis of antibiotics: Inhibition of protein synthesis versus DNA synthesis

In this piece of writing, we will be addressing the following factors: properties of antibiotics, mechanism of action, clinical safety profile, as well as toxicity, adverse event profile, and case fatality rate. From our evaluation, in terms of properties of the two groups of antibiotics, protein synthesis-inhibiting antibiotics displays a like number of lipophilic and hydrophilic properties, with the majority of Anti-30S inhibitor drugs being predominantly hydrophilic, and a higher number of lipophilic drugs amongst Anti-50S inhibitors. Anti-50S inhibitors could therefore be preferred in oral intake drug development. DNA synthesis-inhibiting antibiotics show a limited trend in their properties. The mechanism of action for protein synthesis-inhibiting antibiotics generally follows four steps: activation of amino acids, initiation, extension, and termination of peptide chain synthesis. On the other hand, DNA synthesis-inhibiting antibiotics exhibits a range of different mechanisms, all of which results in the damage of DNA structure of the bacterium. In both clinical safety and toxicity studies, it is concluded that the two groups of antibiotics have previous cases of side effects, with the DNA synthesis-inhibiting drug, fluoroquinolones, more dangerous due to its potential to result in ventricular fibrillation on a patient. By assessing and comparing all the factors, this review aims to present a precise comparison of the similarities and differences between the protein and DNA synthesis inhibitors, and an evaluation of the effectiveness of the two groups against bacterial infections, along with their safety for regular medication use.

Fatty Acid Esters and Acyclic Monoterpenoid from Justicia insularis Leaf Fractions Attenuated Malaria Pathogenesis Through Docking with Plasmodium falciparum Serine Hydroxymethyl Transferase and Plasmodium falciparum Erythrocyte Membrane Protein 1 Proteins

Background Justicia insularis (Acanthaceae) T. Anderson is ethnopharmacologically used in Nigeria for the treatment of diseases including malaria. Therefore, this study was designed to investigate in vivo antiplasmodial effect of J. insularis leaf in Plasmodium berghei-infected mice, characterize its constituents, and carryout in silico studies of its compounds. Methods Standard protocols were followed in the processing of the plant leaves, extraction, fractionation, isolation, and characterization, evaluation of in vivo antiplasmodial assay, retrieval of Plasmodium falciparum serine hydroxymethyl transferase (PfSHMT) and Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1) proteins, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and docking studies. Gas chromatography-mass spectrometry (GC-MS) was employed to isolate and characterize the compounds; SWISSADME and ADMET lab 2 enhanced the evaluation of pharmacokinetic properties, PyRx for docking analysis; Biovia discovery studio for 2D visualization, and PyMol software for 3D visualization of the ligand-protein interactions. Results The dichloromethane (61.59%) and ethyl acetate (73.15%) fractions had the best therapeutic indices and compared favorably with chloroquine (81.58%) in the curative antiplasmodial assay. The GC-MS analysis revealed 20 already reported antiplasmodial compounds with hexanoic acid 1,1-dimethylethyl ester, octadecanoic acid docosyl ester, and trans-β-ocimene as the lead compounds based on their binding affinities, permeation of the blood-brain-barrier, non-inhibition of metabolizing enzymes, ease of excretion, non-carcinogenicity, as well as non-violation of Lipinski's criteria. Conclusion Octadecanoic acid docosyl ester and hexanoic acid 1,1-dimethylethyl ester bonded the tetrahydrofolate-binding sites of PfSHMT, caused inhibition of DNA synthesis, and apoptosis, whereas trans-β-ocimene inhibited PfEMP-1, reversed the attachment of parasitized red blood cells to micro-vascular endothelium as their mechanism of action for parasitemia clearance. Moreover, these lead compounds reported for the first time in the dichloromethane and EtoAc fractions of this plant are responsible for the remarkable antiplasmodial activity observed in this study.

Potential therapeutic agents of Bombyx mori silk cocoon extracts from agricultural product for inhibition of skin pathogenic bacteria and free radicals.

Pathogenic bacteria are the cause of most skin diseases, but issues such as resistance and environmental degradation drive the need to research alternative treatments. It is reported that silk cocoon extract possesses antioxidant properties. During silk processing, the degumming of silk cocoons creates a byproduct that contains natural active substances. These substances were found to have inhibitory effects on bacterial growth, DNA synthesis, the pathogenesis of hemolysis, and biofilm formation. Thus, silk cocoon extracts can be used in therapeutic applications for the prevention and treatment of skin pathogenic bacterial infections. The extract of silk cocoons with pupae (SCP) and silk cocoons without pupae (SCWP) were obtained by boiling with distilled water for 9 h and 12 h, and were compared to silkworm pupae (SP) extract that was boiled for 1 h. The active compounds in the extracts, including gallic acid and quercetin, were determined using high-performance liquid chromatography (HPLC). Furthermore, the total phenolic and flavonoid content in the extracts were investigated using the Folin-Ciocalteu method and the aluminum chloride colorimetric method, respectively. To assess antioxidant activity, the extracts were evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Additionally, the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of silk extracts and phytochemical compounds were determined against skin pathogenic bacteria. This study assessed the effects of the extracts and phytochemical compounds on growth inhibition, biofilm formation, hemolysis protection, and DNA synthesis of bacteria. The HPLC characterization of the silk extracts showed gallic acid levels to be the highest, especially in SCP (8.638-31.605 mg/g extract) and SP (64.530 mg/g extract); whereas quercetin compound was only detected in SCWP (0.021-0.031 mg/g extract). The total phenolics and flavonoids in silk extracts exhibited antioxidant and antimicrobial activity. Additionally, SCP at 9 h and 12 h revealed the highest anti-bacterial activity, with the lowest MIC and MBC of 50-100 mg/mL against skin pathogenic bacteria including Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Cutibacterium acnes and Pseudomonas aeruginosa. Hence, SCP extract and non-sericin compounds containing gallic acid and quercetin exhibited the strongest inhibition of both growth and DNA synthesis on skin pathogenic bacteria. The suppression of bacterial pathogenesis, including preformed and matured biofilms, and hemolysis activity, were also revealed in SCP extract and non-sericin compounds. The results show that the byproduct of silk processing can serve as an alternative source of natural phenolic and flavonoid antioxidants that can be used in therapeutic applications for the prevention and treatment of pathogenic bacterial skin infections.

Characteristic effect of hydroxyurea on the higher-order structure of DNA and gene expression

Hydroxyurea (HU; hydroxycarbamide) is a chemotherapy medication used to treat various types of cancer and other diseases such as sickle cell anemia. HU inhibits DNA synthesis by targeting ribonucleotide reductase (RNR). Recent studies have suggested that HU also causes oxidative stress in living systems. In the present study, we investigated if HU could directly affect the activity and/or conformation of DNA. We measured in vitro gene expression in the presence of HU by adapting a cell-free luciferase assay. HU exhibited a bimodal effect on gene expression, where promotion or inhibition were observed at lower or higher concentrations (mM range), respectively. Using atomic force microscopy (AFM), the higher-order structure of DNA was revealed to be partially-thick with kinked-branching structures after HU was added. An elongated coil conformation was observed by AFM in the absence of HU. Single DNA molecules in bulk aqueous solution under fluctuating Brownian motion were imaged by fluorescence microscopy (FM). Both spring and damping constants, mechanical properties of DNA, increased when HU was added. These experimental investigations indicate that HU directly interacts with DNA and provide new insights into how HU acts as a chemotherapeutic agent and targets other diseases.

Potential applications of antofine and its synthetic derivatives in cancer therapy: structural and molecular insights.

Cancer is a major global health challenge, being the second leading cause of morbidity and mortality after cardiovascular disease. The growing economic burden and profound psychosocial impact on patients and their families make it urgent to find innovative and effective anticancer solutions. For this reason, interest in using natural compounds to develop new cancer treatments has grown. In this respect, antofine, an alkaloid class found in Apocynaceae, Lauraceae, and Moraceae family plants, exhibits promising biological properties, including anti-inflammatory, anticancer, antiviral, and antifungal activities. Several molecular mechanisms have been identified underlying antofine anti-cancerous effects, including the inhibition of nuclear factor κB (NF-κB) and AKT/mTOR signaling pathways, epigenetic inhibition of protein synthesis, ribosomal targeting, induction of apoptosis, inhibition of DNA synthesis, and cell cycle arrest. This study discusses the molecular structure, sources, photochemistry, and anticancer properties of antofine in relation to its structure-activity relationship and molecular targets. Then, examine in vitro and in vivo studies and analyze the mechanisms of action underpinning antofine efficacy against cancer cells. This review also discusses multidrug resistance in human cancer and the potential of antofine in this context. Safety and toxicity concerns are also addressed as well as current challenges in antofine research, including the need for clinical trials and bioavailability optimization. This review aims to provide comprehensive information for more effective natural compound-based cancer treatments.

Adenovirus-mediated expression of MOAP-1, Bax and RASSF1A antagonizes chemo-drug resistance of human breast cancer cells expressing cancer stem cell markers

Cancer is one of the major leading causes of mortality globally and chemo-drug-resistant cancers pose significant challenges to cancer treatment by reducing patient survival rates and increasing treatment costs. Although the mechanisms of chemoresistance vary among different types of cancer, cancer cells are known to share several hallmarks, such as their resistance to apoptosis as well as the ability of cancer stem cells to produce metastatic daughter cells that are resistant to chemotherapy. To address the issue of chemo-drug resistance in cancer cells, a tetracistronic expression construct, Ad-MBR-GFP, encoding adenovirus-mediated expression of MOAP-1, Bax, RASSSF1A, and GFP, was generated to investigate its potential activity in reducing or inhibiting the chemo-drug resistant activity of the human breast cancer cells, MCF-7-CR and MDA-MB-231. When infected by Ad-MBR-GFP, the cancer cells exhibited round cell morphology and nuclei condensation with positive staining for annexin-V. Furthermore, our results showed that both MCF-7-CR and MDA-MB-231 cells stained positively for CD 44 and negatively for CD 24 (CD44+/CD24-) with high levels of endogenous ALDH activity whereas SNU-1581 breast cancer cells were identified as CD 44-/CD 24- cells with relatively low levels of endogenous ALDH activity and high sensitivity toward chemo-drugs, suggesting that both CD 44 and ALDH activity contribute to chemo-drug resistance. Moreover, both MCF-7-CR and MDA-MB-231 cells showed strong chemo-drug sensitivity to cisplatin when the cells were infected by Ad-MBR-GFP, leading to 9-fold and 2-fold reduction in the IC 50 values when compared to cisplatin treatment alone, respectively. The data were further supported by 3D (soft agar) and spheroid cell models of MCF-7-CR and MDA-MB-231 cells which showed a 2-fold reduction of a number of cell colonies and spheroid size when treated with both Ad-MBR-GFP and cisplatin, and compared to control. Other than chemo-sensitivity, Ad-MBR-GFP-infected cancer cells retarded cell migration. Flow cytometry analysis showed that the mechanism of action of Ad-MBR-GFP involved cell cycle arrest at the G1 phase and inhibition of cellular DNA synthesis. Taken together, our investigation showed that Ad-MBR-GFP mediated chemo-drug sensitization in the infected cancer cells involved the activation of apoptosis signaling, cell cycle arrest, and inhibition of DNA synthesis, suggesting that Ad-MBR-GFP is potentially efficacious for the treatment of chemo-drug resistant cancers.