QSAR, ADMET, molecular docking, and dynamics studies of 1,2,4-triazine-3(2H)-one derivatives as tubulin inhibitors for breast cancer therapy.

Breast cancer remains a leading cause of cancer-related deaths among women globally, necessitating the development of more effective therapeutic agents with minimal side effects. This study explores novel 1,2,4-triazine-3(2H)-one derivatives as potential inhibitors of Tubulin, a pivotal protein in cancer cell division, highlighting a targeted approach in cancer therapy. Using an integrated computational approach, we combined quantitative structure-activity relationship (QSAR) modeling, ADMET profiling, molecular docking, and molecular dynamics simulations to evaluate and predict the efficacy and stability of these compounds. Our QSAR models, developed through rigorous statistical analysis, revealed that descriptors such as absolute electronegativity and water solubility significantly influence inhibitory activity, achieving a predictive accuracy (R2) of 0.849. Molecular docking studies identified compounds with high binding affinities, particularly Pred28, which exhibited the best docking score of - 9.6 kcal/mol. Molecular dynamics simulations conducted over 100 ns provided further insights into the stability of these interactions. Pred28 demonstrated notable stability, with the lowest root mean square deviation (RMSD) of 0.29 nm and root mean square fluctuation (RMSF) values indicative of a tightly bound conformation to Tubulin. The novelty of this work lies in its methodological rigor and the integration of multiple advanced computational techniques to pinpoint compounds with promising therapeutic potential. Our findings advance the current understanding of Tubulin inhibitors and open avenues for the synthesis and experimental validation of these compounds, aiming to offer new solutions for breast cancer treatment.

Therapeutic potential and action mechanisms of licochalcone B: a mini review.

Licochalcone B (LicB), a chalcone derived from Glycyrrhiza uralensis and Glycyrrhiza glabra, has received considerable attention due to its diverse pharmacological properties. Accumulated data indicates that LicB has pharmacological effects that include anti-cancer, hepatoprotective, anti-inflammatory, and neuroprotective properties. The action mechanism of LicB has been linked to several molecular targets, such as phosphoinositide 3-kinase/Akt/mammalian target of rapamycin, p53, nuclear factor-κB, and p38, and the involvements of caspases, apoptosis, mitogen-activated protein kinase-associated inflammatory pathways, and anti-inflammatory nuclear factor erythroid 2-related factor 2 signaling pathways highlight the multifaceted therapeutic potential of LicB. This review systematically updates recent findings regarding the pharmacological effects of LicB, and the mechanistic pathways involved, and highlights the potential use of LicB as a promising lead compound for drug discovery.

Plant bioactive compounds driven microRNAs (miRNAs): A potential source and novel strategy targeting gene and cancer therapeutics.

Irrespective of medical technology improvements, cancer ranks among the leading causes of mortality worldwide. Although numerous cures and treatments exist, creating alternative cancer therapies with fewer adverse side effects is vital. Since ancient times, plant bioactive compounds have already been used as a remedy to heal cancer. These plant bioactive compounds and their anticancer activity can also deregulate the microRNAs (miRNAs) in the cancerous cells. Therefore, the deregulation of miRNAs in cancer cells by plant bioactive compounds and the usage of the related miRNA could be a promising approach for cancer cure, mainly to prevent cancer and overcome chemotherapeutic side effect problems. Hence, this review highlights the function of plant bioactive compounds as an anticancer agent through the underlying mechanism that alters the miRNA expression in cancer cells, ultimately leading to apoptosis. Moreover, this review provides insight into using plant bioactive compounds -driven miRNAs as an anticancer agent to develop miRNA-based cancer gene therapy. They can be the potential resource for gene therapy and novel strategies targeting cancer therapeutics.

Sorbate metal complexes as newer antibacterial, antibiofilm, and anticancer compounds.

BACKGROUND: The ineffectiveness of treatments for infections caused by biofilm-producing pathogens and human carcinoma presents considerable challenges for global public health organizations. To tackle this issue, our study focused on exploring the potential of synthesizing new complexes of Co(II), Cu(II), Ni(II), and Zn(II) with sorbic acid to enhance its antibacterial, antibiofilm, and anticancer properties. METHODS: Four novel complexes were synthesized as solid phases by reacting sorbic acid with Co(II), Cu(II), Ni(II), and Zn(II). These complexes were characterized by various technique, including infrared spectra, UV-Visible spectroscopy, proton nuclear magnetic resonance (1H NMR), and thermal analysis techniques, including thermogravimetry (TG). RESULTS: The data acquired from all investigated chemical characterization methods confirmed the chemical structure of the sorbate metal complexes. These complexes exhibited antibacterial and antibiofilm properties against both Gram-positive and Gram-negative bacteria. Furthermore, these complexes enhanced the antibacterial effects of commonly used antibiotics, such as gentamicin and imipenem, with fractional inhibitory concentration (FIC) indices ≤ 0.5. Notably, the Cu(II) complex displayed the most potent antibacterial and antibiofilm activities, with minimum inhibitory concentration (MIC) values of 312.5 µg/mL and 625.0 µg/mL for Bacillus cereus and Escherichia coli, respectively. Additionally, in vitro assays using the methyl thiazolyl tetrazolium (MTT) method showed inhibitory effects on the growth of the human colon carcinoma cell line (HCT-116 cells) following treatment with the investigated metal complexes. The IC50 values for Co(II), Cu(II), Zn(II), and Ni(II) were 3230 µg/mL, 2110 µg/mL, 3730 µg/mL, and 2240 µg/mL, respectively. CONCLUSION: Our findings offer potential for pharmaceutical companies to explore the development of novel combinations involving traditional antibiotics or anticancer drugs with sorbate copper complex.

Rosmarinic acid modulates purinergic signaling and induces apoptosis in melanoma cells.

Cancer cases have increased worldwide. Cutaneous melanoma (CM), a highly metastatic skin cancer, largely contributes to global statistical cancer death data. Research has shown that rosmarinic acid (RA) is a promising phenolic compound with antineoplastic properties. Thus, we investigated the effects of RA on apoptosis-inducing in melanoma cells, purinergic signaling modulation, and cytokine levels. We treated SK-MEL-28 cells for 24 h with different concentrations of RA and assessed the apoptosis, CD39, CD73, and A2A expression, and cytokine levels. We found RA-induced apoptosis in melanoma cells. Regarding the purinergic system, we verified that RA downregulated the expression of CD73 and A2A, specially at high concentrations of treatment. Additionally, RA increased IL-6, IL-4, IL-10, IFN-γ, and TNF-α levels. Our in vitro results confirm RA's potential to be used to induce melanoma cell apoptosis, having CD73 and A2A as targets when reversion of immune suppression is desired. Further studies in animal models and clinical trials focusing on RA's modulation of purinergic signaling in melanoma are required.

Genetic engineering of Salmonella spp. for novel vaccine strategies and therapeutics.

Salmonella enterica is a diverse species that infects both humans and animals. S. enterica subspecies enterica consists of more than 1,500 serovars. Unlike typhoidal Salmonella serovars which are human host-restricted, non-typhoidal Salmonella (NTS) serovars are associated with foodborne illnesses worldwide and are transmitted via the food chain. Additionally, NTS serovars can cause disease in livestock animals causing significant economic losses. Salmonella is a well-studied model organism that is easy to manipulate and evaluate in animal models of infection. Advances in genetic engineering approaches in recent years have led to the development of Salmonella vaccines for both humans and animals. In this review, we focus on current progress of recombinant live-attenuated Salmonella vaccines, their use as a source of antigens for parenteral vaccines, their use as live-vector vaccines to deliver foreign antigens, and their use as therapeutic cancer vaccines in humans. We also describe development of live-attenuated Salmonella vaccines and live-vector vaccines for use in animals.

pH-tailored delivery of a multitarget anticancer benzimidazole derivative using a PEGylated ß-cyclodextrin-curcumin functionalized nanocomplex.

In this study, we aimed to enhance the bioavailability of a benzimidazole derivative with potent anticancer potential through a nano-based approach. Benzimidazole-loaded polyethylene glycol-ß-cyclodextrin-functionalized curcumin nanocomplex (BMPE-Cur) was prepared and characterized for its physicochemical properties and drug release profiles under different pH conditions. In addition, the biological activities of the nanocomplex including antioxidant potentials and pro-apoptogenic properties, against HepG2, PC3, and the chemo-resistant MCF-7-ADR cell lines relative to the normal Wi-38 cell line were in vitro assessed and compared with those of the free benzimidazole compound. In addition to FTIR, XRD, and NMR spectral studies, a polymeric nanocomplex with an average particle size of 467.7 nm and high stability was successfully developed, as indicated by the negative zeta potential (-28.24 mV). The nanocomplex also showed prolonged pH-sensitive sustained drug release under conditions that replicated the tumor's extra/intracellular pH. The formulated nanocomplex also demonstrated potent radical scavenging capacity owing to the inclusion of curcumin, a known radical quencher. In addition, compared with the free compound, BMPE-Cur induced DNA fragmentation-driven cell cycle arrest in HepG2, PC3, and MCF-7-ADR cells at the G1/S, G1 & S phases; respectively, with remarkable selectivity. In conclusion, the newly formulated BMPE-Cur nanocomplex represents an attractive multitarget anticancer candidate.

A Novel Pyrazole Exhibits Potent Anticancer Cytotoxicity via Apoptosis, Cell Cycle Arrest, and the Inhibition of Tubulin Polymerization in Triple-Negative Breast Cancer Cells.

In this study, we screened a chemical library to find potent anticancer compounds that are less cytotoxic to non-cancerous cells. This study revealed that pyrazole PTA-1 is a potent anticancer compound. Additionally, we sought to elucidate its mechanism of action (MOA) in triple-negative breast cancer cells. Cytotoxicity was analyzed with the differential nuclear staining assay (DNS). Additional secondary assays were performed to determine the MOA of the compound. The potential MOA of PTA-1 was assessed using whole RNA sequencing, Connectivity Map (CMap) analysis, in silico docking, confocal microscopy, and biochemical assays. PTA-1 is cytotoxic at a low micromolar range in 17 human cancer cell lines, demonstrating less cytotoxicity to non-cancerous human cells, indicating a favorable selective cytotoxicity index (SCI) for the killing of cancer cells. PTA-1 induced phosphatidylserine externalization, caspase-3/7 activation, and DNA fragmentation in triple-negative breast MDA-MB-231 cells, indicating that it induces apoptosis. Additionally, PTA-1 arrests cells in the S and G2/M phases. Furthermore, gene expression analysis revealed that PTA-1 altered the expression of 730 genes at 24 h (198 upregulated and 532 downregulated). A comparison of these gene signatures with those within CMap indicated a profile similar to that of tubulin inhibitors. Subsequent studies revealed that PTA-1 disrupts microtubule organization and inhibits tubulin polymerization. Our results suggest that PTA-1 is a potent drug with cytotoxicity to various cancer cells, induces apoptosis and cell cycle arrest, and inhibits tubulin polymerization, indicating that PTA-1 is an attractive drug for future clinical cancer treatment.

Pyrazole, Pyrazoline, and Fused Pyrazole Derivatives: New Horizons in EGFR-Targeted Anticancer Agents.

Pyrazole and its derivatives remain popular heterocycles in drug design, and development. Pyrazole derivatives been extensively studied by the scientific community and as they possess a wide range of biological activity, especially anti-EGFR properies. Overexpression of EGFR signaling promotes tumor growth by inhibiting apoptosis. EGFR dysfunction has been described in several cancer. Therefore, EGFR represents a prospective target for cancer treatment. Several anti-EGFR drugs are thriving the market, notably dacomitinib, afatinib, erlotinib etc. However, almost all drugs have limited therapeutic effectiveness due to a lack of selectivity as well as substantial side effects.  To address this, innovative therapeutic anti-EGFR drugs with high effectiveness and low toxicity are needed. To combat therapeutic resistance to EGFR inhibitors, pyrazole, and pyrazole-based derivatives have been explored as a promising pharmacophore for developing novel compounds with higher potency, lower toxicity, and desirable pharmacokinetic profiles. The current review outlines the investigation of advancements towards anti- EGFR via pyrazole, pyrazoline, and fused pyrazole-based compounds and represents inclusive data on pyrazole-based marketed drugs as well as therapeutic candidates undergoing preclinical and clinical development. We have also summarised structure-activity relationship (SAR), mechanistic studies to afford ideas for the design and development of new anti-EGFR derivatives.

An In Vitro Investigation of the Antiproliferative and Antimetastatic Effects of Levosimendan: Potential Drug Repurposing for Cervical Cancer.

Cervical cancer presents a significant challenge to the global health of women. Despite substantial advances in human papillomavirus (HPV)-related cervical cancer vaccines, non-HPV-related cervical cancer is still waiting novel therapeutic options. Drug repurposing has provided a promising approach to improve cancer therapy in recent years. Our study aimed to explore the potential in vitro antineoplastic effects of levosimendan on cervical cancer cells. The antiproliferative effects of levosimendan were investigated on cervical cancer cells using a standard MTT assay. Fluorescent double staining was performed to identify its ability to induce apoptosis and necrosis. The possible mechanism of action of levosimendan was explored using cell-cycle analysis. Furthermore, antimetastatic effects were investigated using a wound-healing assay and a Boyden chamber assay. Our results revealed that levosimendan exhibited the highest growth-inhibitory effect in the HPV-negative C33A cell line. However, the effects were modest compared to the standard agent, cisplatin. Cell-cycle analysis detected that levosimendan can induce cell-cycle arrest in C33A cells by increasing the G1 and G2/M phases, decreasing the S phase, and enhancing the hypodiploid subG1 population. Levosimendan inhibited cell migration and invasion in a concentration-dependent manner. As levosimendan showed antimetastatic efficacy, it could be considered for repurposing to contribute to overcoming resistance to therapy in cervical cancer.

Chemopreventive Agents from Nature: A Review of Apigenin, Rosmarinic Acid, and Thymoquinone.

Cancer, a major challenge to global health and healthcare systems, requires the study of alternative and supportive treatments due to the limitations of conventional therapies. This review examines the chemopreventive potential of three natural compounds: rosmarinic acid, apigenin, and thymoquinone. Derived from various plants, these compounds have demonstrated promising chemopreventive properties in in vitro, in vivo, and in silico studies. Specifically, they have been shown to inhibit cancer cell growth, induce apoptosis, and modulate key signaling pathways involved in cancer progression. The aim of this review is to provide a comprehensive overview of the current research on these phytochemicals, elucidating their mechanisms of action, therapeutic efficacy, and potential as adjuncts to traditional cancer therapies. This information serves as a valuable resource for researchers and healthcare providers interested in expanding their knowledge within the field of alternative cancer therapies.

Temozolomide (TMZ) in the Treatment of Glioblastoma Multiforme-A Literature Review and Clinical Outcomes.

Glioblastoma multiforme (GBM) is one of the most aggressive primary tumors of the central nervous system. It is associated with a very poor prognosis, with up to half of patients failing to survive the first year after diagnosis. It develops from glial tissue and belongs to the adult-type diffuse glioma group according to the WHO classification of 2021. Therapy for patients with GBM is currently based on surgical resection, radiation therapy, and chemotherapy, but despite many efforts, there has been minimal progress in tumor management. The most important chemotherapeutic agent in the treatment of this tumor is temozolomide (TMZ), a dacarbazine derivative that presents alkylating activity. It is usually administered to patients concurrently with radiation therapy after surgical resection of the tumor, which is defined as the Stupp protocol. Temozolomide demonstrates relatively good efficacy in therapy, but it could also present with several side effects. The resistance of GBM to the drug is currently the subject of work by specialists in the field of oncology, and its use in various regimens and patient groups may bring therapeutic benefits in the future. The aim of this review paper is to summarize the relevance of TMZ in the treatment of GBM based on recent reports.

Ganoderma pfeifferi Bres. and Ganoderma resinaceum Boud. as Potential Therapeutic Agents: A Comparative Study on Antiproliferative and Lipid-Lowering Properties.

Medicinal mushrooms, especially Ganoderma species, hold immense promise for the production of a wide range of bioactive compounds with various effects. The biochemical potential of indigenous fungal strains, specific to a region, could play a critical role in the continuous search for novel strains with superior activities on a global scale. This research focused on the ethanolic (EtOH) and hot-water (H2O) extracts of fruiting bodies of two wild-growing Ganoderma species: G. pfeifferi and G. resinaceum, with the aim of assessing their nutritional (total carbohydrate content-TCC) and mineral composition in relation to bioactive properties: antioxidant, antiproliferative and lipid-lowering. Atomic absorption spectrophotometry (AAS) revealed that G. pfeifferi is a promising source of minerals that are essential for numerous physiological functions in the human body like bone health and muscle and nerve function, with Ca (4.55 ± 0.41 mg/g d.w.) and Mg (1.33 ± 0.09 mg/g d.w.) being the most abundant macroelement present. Zn, Mn, and Cr were particularly notable, with concentrations ranging from 21.49 to 41.70 mg/kg d.w. The EtOH extract of G. pfeifferi demonstrated significantly elevated levels of TCC, essential macromolecules for energy and structural functions in the body, with higher quantities of all three standard carbohydrates detected in this type of extract. Similar to the revealed composition, the same species, G. pfeifferi, stood out as the most prominent antioxidant agent, with the H2O extract being stronger than EtOH in the ABTS assay (86.85 ± 0.67 mg TE/g d.w.), while the EtOH extract displayed the highest anti-OH• scavenging ability (IC50 = 0.18 ± 0.05 µg/mL) as well as the most notable reducing potential among all. The highest antiproliferative effect against the breast cancer cell line (MCF-7), were demonstrated by the H2O extracts from G. resinaceum with the most pronounced activity after 24 h (IC50 = 4.88 ± 0.50 µg/mL), which surpasses that of the standard compound, ellagic acid (IC50 = 33.94 ± 3.69 µg/mL). Administration of both Ganoderma extracts mitigated diabetic lipid disturbances and exhibited potential renal and hepatic protection in vivo on white Wistar rats by the preservation of kidney function parameters in G. resinaceum H2O pre-treatment (urea: 6.27 ± 0.64 mmol/L, creatinine: 50.00 ± 6.45 mmol/L) and the reduction in ALT levels (17.83 ± 3.25 U/L) compared to diabetic control groups treated with saline (urea: 46.98 ± 6.01 mmol/L, creatinine: 289.25 ± 73.87 mmol/L, and ALT: 60.17 ± 9.64 U/L). These results suggest that pre-treatment with G. resinaceum H2O extracts may have potential antidiabetic properties. In summary, detected microelements are vital for maintaining overall health, supporting metabolic processes, and protecting against various chronic diseases. Further research and dietary assessments could help determine the full potential and applications of the two underexplored Ganoderma species native to Serbia in nutrition and health supplements.

Unlocking the biological potential of transition metal complexes with Thiosemicarbazone ligands: Insights from computational studies.

In the previous study, the synthesis and characterization of 4-(3-fluorophenyl)-3-thiosemicarbazide and benzaldehyde derivatives based thiosemicarbazone ligands and their Co(II), Ni(II), Cu(II), Zn(II) complexes were carried out to evaluate their malarial and oxidant and inflammatory inhibition abilities, demonstrating that these compounds have robust efficacy for these ailments. In the present research, to find out a combating agent against breast cancer, tuberculosis, bacterial and fungal ailments, the compounds were tested through MTT, microplate alamar blue and serial dilution protocols. ADMET and DFT investigation were analyzed against highly bioactive compounds (2, 7-10) to give a new insight about compound's reactivity, stability and drug likeness properties. Furthermore, activity results shows that the ligand (2) and its complexes demonstrate greater efficacy compared to ligand (1) and its complexes. The Cu(II) (9) and Zn(II) (10) complexes were observed as highly efficient for breast cancer (MCF-7 cell line), TB (H37Rv strain), bacterial and fungal ailments in comparison of standard drugs with 0.029 ± 0.001 µM IC50 value for (9) in anticancer activity and 0.0034 ± 0.0017 µmol/mL MIC value for (10) in anti-tuberculosis activity. In the molecular docking investigation, the various kind of binding interactions and lowest binding affinity of (9) (against 4RJ3 (-10.0 kcal/mol), 2VCJ (-7.9 kcal/mol)) and (10) (-7.8 and -8.3 kcal/mol for 5V3Y and 3PTY protein) support their bioactivity. This research highlights the pharmaceutical importance of transition metal complexes having thiosemicarbazones, presenting a significant approach for the discovery of potent anti-infectious agent.

Impacts of designed vanillic acid-polymer-magnetic iron oxide nanocomposite on breast cancer cells.

The engineered nano-vehicle was constructed using magnetic iron oxide nanoparticles (MIONs) and chitosan (CTS) to stabilize anticancer agent vanillic acid (VNA) which was loaded on CTS-coated MIONs nanocarrier, and more importantly, to achieve sustained VNA release and subsequent proper anticancer activity. The new thermally stable VNA-CTS- MIONs nanocomposite was spherical with a middle diameter of 6 nm and had a high drug loading of about 11.8 %. The MIONs and resulting nanocomposite were composed of pure magnetite and therefore, were superparamagnetic with saturation magnetizations of 53.3 and 45.7 emu.g-1, respectively. The release profiles of VNA from VNA-CTS-MIONs nanocomposite in different pH values were sustained and showed controlled pH-responsive delivery of the loaded VNA with 89 % and 74 % percentage release within 2354 and 4046 min at pH 5 and 7.4, respectively, as well as were in accordance with the pseudo-second-order model. The VNA-CTS-MIONs nanocomposite treatment at diverse concentrations remarkably decreased the viability and promoted ROS accumulation and apoptosis in the MDA-MB-231 breast cancer cells. Hence, it can be a propitious candidate for the management of breast cancer in the future.

Stabilized, ROS-sensitive ß-cyclodextrin-grafted hyaluronic supramolecular nanocontainers for CD44-targeted anticancer drug delivery.

Hyaluronic acid (HA)-based tumor microenvironment-responsive nanocontainers are attractive candidates for anticancer drug delivery due to HA's excellent biocompatibility, biodegradability, and CD44-targeting properties. Nevertheless, the consecutive synthesis of stabilized, stealthy, responsive HA-based multicomponent nanomedicines generally requires multi-step preparation and purification procedures, leading to batch-to-batch variation and scale-up difficulties. To develop a facile yet robust strategy for promoted translations, a silica monomer containing a cross-linkable diethoxysilyl unit was prepared to enable in situ crosslinking without any additives. Further combined with the host-guest inclusion complexation between ß-cyclodextrin-grafted HA (HA-CD) and ferrocene-functionalized polymers, ferrocene-terminated poly(oligo(ethylene glycol) methyl ether methacrylate (Fc-POEGMA) and Fc-terminated poly(ε-caprolactone)-b-poly(3-(diethoxymethylsilyl)propyl(2-(methacryloyloxy)ethyl) carbamate) (Fc-PCL-b-PDESPMA), a reactive oxygen species (ROS)-sensitive supramolecular polymer construct, Fc-POEGMA/Fc-PCL-b-PDESPMA@HA-CD was readily fabricated to integrate stealthy POEGMA, tumor active targeting HA, and an in situ cross-linkable PDESPMA sequence. Supramolecular amphiphilic copolymers with two different POEGMA contents of 25 wt% (P1) and 20 wt% (P2) were prepared via a simple physical mixing process, affording two core-crosslinked (CCL) micelles via an in situ sol-gel process of ethoxysilyl groups. The P1-based CCL micelles show not only desired colloidal stability against high dilution, but also an intracellular ROS-mimicking environment-induced particulate aggregation that is beneficial for promoted intracellular release of the loaded cargoes. Most importantly, P1-based nanomedicines exhibited greater cytotoxicity in CD44 receptor-positive HeLa cells than that in CD44 receptor-negative MCF-7 cells. Overall, this work developed HA-based nanomedicines with sufficient extracellular colloidal stability and efficient intracellular destabilization properties for enhanced anticancer drug delivery via smart integration of in situ crosslinking and supramolecular complexation.

Exploring quinoxaline derivatives: An overview of a new approach to combat antimicrobial resistance.

Antimicrobial resistance (AMR) has emerged as a long-standing global issue ever since the introduction of penicillin, the first antibiotic. Scientists are constantly working to develop innovative antibiotics that are more effective and superior. Unfortunately, the misuse of antibiotics has resulted in their declining effectiveness over the years. By 2050, it is projected that approximately 10 million lives could be lost annually due to antibiotic resistance. Gaining insight into the mechanisms behind the development and transmission of AMR in well-known bacteria including Escherichia coli, Bacillus pumilus, Enterobacter aerogenes, Salmonella typhimurium, and the gut microbiota is crucial for researchers. Environmental contamination in third world and developing countries also plays a significant role in the increase of AMR. Despite the availability of numerous recognized antibiotics to combat bacterial infections, their effectiveness is diminishing due to the growing problem of AMR. The overuse of antibiotics has led to an increase in resistance rates and negative impacts on global health. This highlights the importance of implementing strong antimicrobial stewardship and improving global monitoring, as emphasized by the World Health Organization (WHO) and other organizations. In the face of these obstacles, quinoxaline derivatives have emerged as promising candidates. They are characterized by their remarkable efficacy against a broad spectrum of harmful bacteria, including strains that are resistant to multiple drugs. These compounds are known for their strong structural stability and adaptability, making them a promising and creative solution to the AMR crisis. This review aims to assess the effectiveness of quinoxaline derivatives in treating drug-resistant infections, with the goal of making a meaningful contribution to the global fight against AMR.

Thymoquinone, artemisinin, and thymol attenuate proliferation of lung cancer cells as Sphingosine kinase 1 inhibitors.

Sphingosine-1-phosphate (S1P) formed via catalytic actions of sphingosine kinase 1 (SphK1) behaves as a pro-survival substance and activates downstream target molecules associated with various pathologies, including initiation, inflammation, and progression of cancer. Here, we aimed to investigate the SphK1 inhibitory potentials of thymoquinone (TQ), Artemisinin (AR), and Thymol (TM) for the therapeutic management of lung cancer. We implemented docking, molecular dynamics (MD) simulations, enzyme inhibition assay, and fluorescence measurement studies to estimate binding affinity and SphK1 inhibitory potential of TQ, AR, and TM. We further investigated the anti-cancer potential of these compounds on non-small cell lung cancer (NSCLC) cell lines (H1299 and A549), followed by estimation of mitochondrial ROS, mitochondrial membrane potential depolarization, and cleavage of DNA by comet assay. Enzyme activity and fluorescence binding studies suggest that TQ, AR, and TM significantly inhibit the activity of SphK1 with IC50 values of 35.52 µM, 42.81 µM, and 53.68 µM, respectively, and have an excellent binding affinity. TQ shows cytotoxic effect and anti-proliferative potentials on H1299 and A549 with an IC50 value of 27.96 µM and 54.43 µM, respectively. Detection of mitochondrial ROS and mitochondrial membrane potential depolarization shows promising TQ-induced oxidative stress on H1299 and A549 cell lines. Comet assay shows promising TQ-induced oxidative DNA damage. In conclusion, TQ, AR, and TM act as potential inhibitors for SphK1, with a strong binding affinity. In addition, the cytotoxicity of TQ is linked to oxidative stress due to mitochondrial ROS generation. Overall, our study suggests that TQ is a promising inhibitor of SphK1 targeting lung cancer therapy.

The role and molecular mechanism of Trametes Robiniophila Murr(Huaier) in tumor therapy.

ETHNOPHARMACOLOGICAL RELEVANCE: Trametes Robiniophila Murr, commonly known as Huaier, has been extensively documented in ethnopharmacology research in China. Huaier has a long history of clinical usage spanning over 1000 years in China. Traditional clinical application records demonstrate the wide utilization of Huaier for treating various cancers and enhancing the autoimmunity of tumor patients. AIM OF THE REVIEW: The present study provides a comprehensive review of the traditional uses, phytochemical constituents, pharmacological activities, anti-tumor mechanism, and potential applications of Huaier, thereby offering valuable insights for the further development and utilization of this natural product. MATERIALS AND METHODS: This study employed the keywords "Trametes Robiniophila Murr" and "Huaier" to retrieve relevant information on Huaier from various databases, including PubMed, Web of Science, Springer, Science Direct, ACS, Wiley, CNKI, Baidu Scholar, Google Scholar, and ancient materia medica. RESULTS: Trametes Robiniophila Murr (Huaier), a traditional Chinese medicine, has demonstrated significant efficacy in the clinical treatment of various tumors. The primary bioactive constituents of Huaier consist of fungal-derived compounds, including polysaccharides, proteins, ketones, alkaloids, and minerals. The research findings demonstrate that Huaier serves as a reliable adjunctive therapeutic agent by effectively inhibiting cancer cell proliferation, inducing apoptosis in cancer cells, suppressing tumor metastasis, regulating tumor stem cells and immune function. Therefore, it exerts a potent anti-tumor effect when used in conjunction with conventional anti-cancer therapies. CONCLUSIONS: The analysis of traditional uses, phytochemical composition, and pharmacological activity reveals that Huaier exhibits significant potential as a medicinal plant with diverse pharmacological effects. Owing to its numerous advantages, Huaier holds immense promise for application in the domains of tumor prevention and treatment, enhancing both survival time and quality of life among cancer patients.