Search Results (7,526)

Cathinone and its synthetic derivatives are among the most popular drugs worldwide. However, the literature provides data on the medicinal and cytotoxic potential of some of these compounds. These data are extremely limited due to the need to obtain additional permits for laboratory studies. Consequently, the therapeutic potential of cathinones may not have been fully explored. Furthermore, the literature provides data on the reduction or reversal of undesirable biological properties of drugs encapsulated in a bio-compatible carrier and administered through targeted therapy. The current study presents preliminary theoretical and experimental tests for further research on target cathinone–graphene–oxide complexes. A non-psychotropic cathinone model—o-fluorophenylacetic acid—was used. The NMR properties (chemical shifts, spin–spin coupling constants, and T₁ relaxation times) of graphene oxide–F-derivative complexes were measured at an acidic and neutral pH. To analyze the structure and stability of the possible complexes in different environments, molecular modelling was performed with simplified graphene oxide models using density functional theory. Experimental data were compared with theoretical values, and the most stable structures that may account for the observed spectral properties of the studied complexes were presented. The obtained data indicate a stronger tendency towards the formation and stabilization of GO-2-fluorophenylacetic acid complexes in a neutral environment. Full article

Background: Irinotecan hydrochloride (CPT-11) is an important anticancer drug used in a wide range of regimens to treat colorectal and gastric cancers, and one of its severe side effects is delayed diarrhea. Therefore, based on known circadian variations in intestinal function and drug metabolism, we investigated whether CPT-11-induced delayed diarrhea may be attenuated by the time of dosing. Methods: When CPT-11 was administered to rats at 9:00 or 21:00, CPT-11-induced delayed diarrhea was assessed, and concentrations of CPT-11, its active metabolite SN-38, and SN-38 glucuronide (SN-38GL) in blood, intestinal tissues, and intestinal contents were measured. Results: The severity of diarrhea was significantly less in the 21:00 dosing group compared with the 9:00 dosing group. Blood SN-38 concentrations 8 h after the administration of CPT-11 were significantly higher in the 9:00 dosing group than in the 21:00 dosing group. SN-38, which exerts potent cytotoxic effects, circulates enterohepatically. When SN-38 is absorbed from the intestinal mucosa, intestinal tissues may be injured, resulting in delayed diarrhea. CPT-11 and SN-38 concentrations in intestinal tissues and contents 8 h after the administration of CPT-11 were significantly higher in the 9:00 dosing group than in the 21:00 dosing group at all measurement points. This was consistent with more severe CPT-11-induced delayed diarrhea in the 9:00 dosing group. Conclusions: Chronotherapy with CPT-11 may reduce CPT-11-induced delayed diarrhea. These differences in SN-38 concentrations in the intestinal tract at different dosing times may contribute to the time-dependent reduction in CPT-11-induced delayed diarrhea. Full article

Background/Objectives: Metabolic dormancy in biofilms leads to reduced drug efficacy in these communities. Different pharmacokinetics and adverse side effects complicate the simultaneous delivery of multiple drugs at appropriate concentrations to the infection site. This study aimed to develop chitosan-coated mesoporous silica nanoparticles loaded with curcumin and amphotericin B (CS@MSNs-Cur-AmB) and to evaluate their antibiofilm activity combined with antimicrobial photodynamic therapy (PDT) against Streptococcus mutans and Candida albicans dual-species biofilms. Methods: CS@MSNs-Cur-AmB were developed. The structure and morphology of the nanoparticles were evaluated using Fourier transform-infrared spectroscopy (FTIR), zeta potential, field emission scanning electron microscopy (FESEM), and thermogravimetric analysis (TGA). Cytotoxicity toward human gingival fibroblasts was assessed. Colony-forming units per milliliter (CFU/mL) were determined. The metabolic activity of biofilm-forming cells was measured using the tetrazolium (MTT) assay. Results: Physicochemical analyses confirmed the synthesis of CS@MSNs-Cur-AmB, revealing a particle size of 228 nm and thermal stability up to 600 °C. Cytotoxicity assays showed that CS@MSNs-Cur-AmB exhibited good biocompatibility (> 90%). CS@MSNs-Cur-AmB improved antimicrobial activity, which was further enhanced by blue light-emitting diode (LED) irradiation. CS@MSNs-Cur-AmB under LED irradiation showed the strongest effect, reducing metabolic activity to 27.74 ± 4.08% (1 W/cm², 1 min), p < 0.001). Conclusions: Formulating two drugs in nanocarrier systems may improve therapeutic efficacy by increasing local concentration and reducing systemic exposure. This offers an effective strategy for combating oral biofilms. Full article

Cisplatin (Cis) resistance and dose-limiting toxicity remain major challenges in the treatment of cervical cancer, necessitating the development of more effective combination strategies. The effects of gallic acid (GA), alone and in combination with Cis, were evaluated in HeLa cervical cancer cells using cell viability, apoptosis, gene expression, caspase activity, and cytokine profiling assays. Drug interactions were assessed using the Chou–Talalay method. The GA+Cis combination was associated with enhanced cytotoxicity compared to single-agent treatments, with combination index (CI) values ranging from 0.61 to 0.92, indicating synergistic interactions. Selectivity index (SI) values exceeding 2 at 48 h suggested preferential cytotoxicity toward cancer cells. The combination treatment significantly increased apoptotic cell populations and was accompanied by elevated caspase-3 and caspase-9 activities. Gene expression analysis revealed increased BAX and CASP3 levels, along with decreased BCL2 and BIRC5 expression, resulting in an increased BAX/BCL2 ratio. In addition, cell cycle analysis indicated accumulation in the G2/M phase, while cytokine profiling demonstrated reduced levels of pro-inflammatory cytokines and increased IL-10 levels under combination treatment conditions. These findings suggest that GA enhances the biological activity of Cis in cervical cancer cells through coordinated modulation of apoptosis, cell cycle dynamics, and inflammatory signaling. However, these results are based on in vitro observations, and further in vivo and mechanistic studies are required to confirm the therapeutic potential of this combination strategy. Full article

Caloric restriction (CR) is known to activate a broad spectrum of cytoprotective signaling pathways and enhance tissue tolerance to various stressors, including those associated with the cytotoxic effects of pharmaceutical agents. Nephrotoxic drugs, such as aminoglycoside antibiotics, remain a major clinical concern due to their frequent use and potential to cause acute kidney injury (AKI), for which effective preventive strategies are still limited. In this study, we investigated whether CR applied for 5 weeks (4-week pretreatment + 1-week concurrent with AKI induction) can alleviate AKI triggered by the antibiotic gentamicin, with a focus on evaluating changes in antioxidant-related parameters and autophagy-associated signaling during CR-mediated nephroprotection. CR’s nephroprotective effects were evaluated using diagnostic assays, Western blotting, and histological analysis. Additionally, oxidative stress markers and mitochondrial integrity were assessed to analyze the impact of CR on antioxidant-related pathways. CR significantly improved renal function and structure, with reduced kidney injury markers (KIM-1, NGAL) and alleviated histological damage. Critically, CR mitigated oxidative stress, evidenced by decreased thiobarbituric acid reactive substances (TBARS) and protein carbonylation, as well as increased levels of the reduced form of glutathione and activity of glutathione peroxidase (GPx). A lowered Bcl-X_L/X_S ratio was consistent with reduced apoptotic signaling, while reduced leukocyte infiltration reflected attenuated renal inflammation. Additionally, a reduction in mitochondrial DNA (mtDNA) lesions suggested that CR was associated with modulation of mitochondrial and metabolism-related pathways, with concurrent improvements in mitochondrial stability. Our findings demonstrate that CR attenuated gentamicin-induced AKI and was associated with changes in antioxidant-related parameters, reduced mtDNA damage, a decrease in inflammatory cell infiltration, and modulation of autophagy-related signaling. Full article

Background/Objectives: This paper describes the synthesis of silica nanoparticles (SiNPs) and their surface modification with amino and phosphate groups (SiNPs-NH₂-PO₃). The functionalized nanoparticles were subsequently loaded with the anticancer drug 5-fluorouracil (SiNPs-NH₂-PO₃-5-FLU) and further modified with PEG2000 (SiNPs-NH₂-PO₃-5-FLU-PEG2000). Methods: In this study, a one-step, two-phase, sol–gel method carried out at room temperature was used to synthesize the nanoparticles. The size and surface zeta potential of the created SiNPs were determined by DLS measurements. HPLC was used to determine the amount of drug loaded into silica nanoparticles and the drug release profile in two different pH environments (slightly acidic and physiological). Based on physicochemical characteristics, the SiNPs-NH₂-PO₃-5-FLU and SiNPs-NH₂-PO₃-5-FLU-PEG2000 formulations were chosen for comprehensive characterization. The cytotoxicity of the studied complexes was assessed in MCF7 breast cancer cells, while their ability to induce apoptosis in those cells was examined using specific immunofluorescence markers: active caspase-7, active poly(ADP-ribose) polymerase (PARP), and p53 protein. Results: Our findings demonstrate that SiNPs-NH₂-PO₃-5-FLU can induce a stronger apoptotic response than free 5-FLU at equivalent concentrations. We observed that drug release occurs not only under physiological conditions but is further enhanced in a mildly acidic environment (pH 5.0), characteristic of the tumor microenvironment. Conclusions: Most 5-fluorouracil formulations are administered as injectable solutions, resulting in systemic exposure and significant adverse effects. However, their encapsulation within nanoparticles could favor preferential drug release in the acidic tumor microenvironment, thus supporting targeted therapy and reducing toxicity to healthy tissues. Moreover, PEGylation of the nanoformulation allows prolonged and controlled release. Full article

Differentiation therapy holds significant potential for the treatment of multiple myeloma (MM). We previously identified that the aminopeptidase N (APN) inhibitor Bestatin promotes MM cell differentiation. Herein, we elucidate the underlying molecular mechanisms of this process. Utilizing MM1.S, U266, and RPMI-8226 cell lines, a combination of CCK-8 assays, flow cytometry, Wright–Giemsa staining, Western blotting, qRT-PCR, ELISA, APN enzymatic activity analysis, SA-β-gal staining, and bioinformatic analyses revealed elevated APN expression across all cell types. Bestatin treatment induced MM cell differentiation in a concentration-dependent manner, which was accompanied by the upregulation of the differentiation marker CD49e, increased immunoglobulin light chain secretion, elevated cellular senescence, and a concomitant suppression of cell proliferation and APN enzymatic activity. Mechanistically, Bestatin exerts its effects by downregulating the CD79B/BTK signaling pathway, thereby activating the downstream transcription factor STAT3. Consistent with this axis, direct inhibition of CD79B/BTK alone was sufficient to induce differentiation, while blockade of STAT3 completely abrogated the differentiation-promoting effect of Bestatin. The APN-neutralizing antibody (WM15) yielded consistent results with Bestatin, further validating this regulatory axis. Furthermore, both the CD79B/BTK inhibitor Ibrutinib and the STAT3 agonist GCDA potentiated the cytotoxicity of the clinical MM drug Ixazomib. Bestatin itself synergized with Ixazomib and enhanced the anti-proliferative effect of IL-6. In summary, our findings establish that the APN inhibitor Bestatin induces MM cell differentiation via the CD79B/BTK-STAT3 signaling axis. Targeting this pathway represents a promising strategy to enhance the efficacy of Ixazomib, providing a compelling rationale for novel combination therapies in MM. Full article

Background and Objectives: Potential anti-neoplastic effects of resveratrol, which has antioxidant features combined with clomipramine, which has antineoplastic features, or with gemcitabine, used as a nucleoside analog widely used in chemotherapy, were evaluated together and individually on the HL-60 leukemia cells in this in vitro screening study. Materials and Methods: HL-60 cells were treated with gemcitabine, clomipramine, resveratrol, or their combinations at concentrations ranging from 1 to 200 µM. Cell viability was assessed at 24, 48, and 72 h using the trypan blue exclusion method, and results are expressed as a percentage of time-matched untreated controls. Cell proliferation was further evaluated by bromodeoxyuridine (BrdU) immunohistochemical labeling. All experiments were performed in triplicate, and statistical analyses were conducted using one-way analysis of variance (ANOVA) with post hoc comparisons. Results: Gemcitabine markedly reduced HL-60 cell viability at all concentrations and time points (p < 0.001), indicating strong time-dependent cytotoxicity, with a significant drop in BrdU proliferation index at 48 h (p < 0.001). Clomipramine exhibited a biphasic response: high concentrations decreased viability (p < 0.05), while low concentrations allowed partial recovery by 72 h. Resveratrol showed concentration-dependent cytotoxicity, with reduced viability at high concentration and near-control levels at low concentration by 72 h; BrdU indices remained significantly lower than control (p < 0.001). Combination treatments with gemcitabine showed no additive cytotoxic or antiproliferative effects (p > 0.05). A transient enhanced effect was observed in the clomipramine + resveratrol group at 24 h (p < 0.01 vs. clomipramine; p < 0.05 vs. gemcitabine). Conclusions: Gemcitabine, clomipramine, and resveratrol all exhibited inhibitory effects on cell proliferation in HL-60 cell cultures. However, the combination treatments did not show additional cytotoxicity or additive effects. These findings suggest that while each of these compounds individually has the potential to inhibit cell growth, their combined application does not enhance the cytotoxic effects beyond those observed with single treatments. These findings highlight the necessity of a rational approach when considering novel drug combinations. Full article

Background/objectives: This study presents a mechanistic assessment of an anti-HSPG2 monoclonal antibody (AM6) as an antibody–drug conjugate (ADC) carrier in vitro. Methods: Using live-cell confocal imaging with pathway inhibitors, we qualitatively characterized AM6 internalization and trafficking and compared linker/payload configurations for intracellular delivery and in vitro cytotoxicity. Results: AM6 exhibited rapid cellular entry in MDA-MB-231-LM2 cells, with contributions from clathrin-mediated endocytosis and macropinocytosis, followed by accumulation in endo-lysosomal compartments. Consistent with these trafficking observations, AM6 ADCs bearing cleavable linkers and a potent payload (MMAE) produced more pronounced antiproliferative effects in MDA-MB-231-LM2 and other HSPG2-positive tumor cells than non-cleavable constructs, whereas doxorubicin-based ADCs showed limited activity and greater aggregation risk. Conclusions: Overall, the data inform linker/payload selection and highlight considerations for future work, including quantitative internalization, antigen-negative or knockdown controls, and in vivo pharmacology. Full article

Euphorbia clavarioides Boiss. is traditionally used in wound healing and other medicinal applications. Its bioactive compounds and pharmacological potential remain underexplored. This study investigated the phytochemical composition, antioxidant, anti-inflammatory, and anticancer activities of E. clavarioides Boiss. traditionally used in wound healing. Plant extracts were characterized using phytochemical screening, Fourier-transform infrared spectroscopy (FTIR), and liquid chromatography–mass spectrometry (LC-MS). Antioxidant activity was evaluated via DPPH and nitric oxide (NO) scavenging assays, anti-inflammatory effects through nitrite inhibition in LPS-stimulated RAW 264.7 macrophages, and anticancer potential using the MTT assay against DU-145, PC-3, SKU-T, and AGS cell lines. Phytochemical screening confirmed tannins, phlobatannins, saponins, flavonoids, alkaloids, steroids, terpenoids, and cardiac glycosides. FTIR spectra of aqueous extracts revealed peaks at 2990.66 cm⁻¹ (O–H), 1738.68 cm⁻¹ (C=O), 1217.22 cm⁻¹ (C–N), and 527.37 cm⁻¹ (C–Cl). LC-MS profiling identified diverse metabolites, including phenolics (pseudolaroside B, cinnamtannin A2, (−)-medicarpin, butyrolactol A) and terpenoids (zerumbone, sclareol isomer, diterpenoid-like compounds), underpinning the plant’s bioactivity. Methanol extracts exhibited the strongest DPPH scavenging activity (IC₅₀ = 755.71 µg/mL), whereas aqueous and ethanol extracts demonstrated superior NO scavenging. Ethanol extracts showed maximal anti-inflammatory activity, while aqueous extracts induced pro-inflammatory effects. Cytotoxicity assays indicated negligible toxicity. In anticancer assays, ethanol and methanol extracts significantly inhibited the proliferation of all tested cell lines at 100 µg/mL, exceeding drug control, whereas aqueous extracts displayed lower activity. The bioactive compounds in E. clavarioides support its traditional wound-healing use and demonstrate mechanistic antioxidant, anti-inflammatory, and anticancer activities, highlighting its potential as a source of multi-target natural therapeutics. Full article

A strategy to create highly effective antimicrobial agents was proposed based on the conjugation of three functional components: a cationic quaternary ammonium salt (QAS) that exerts a membrane-disrupting effect and promotes selective accumulation on bacterial surfaces; a phosphonamidate linker for controlled activation; and a sterically hindered phenol (SHP) fragment as a potential redox component. This approach enabled the preparation of 40 target phosphonamidate–SHP/QAS hybrids in high yields (88–98%). Evaluation of their antimicrobial activity against major pathogens and methicillin-resistant Staphylococcus aureus (MRSA) revealed high potency against Gram-positive bacteria. The lead compounds achieved minimum inhibitory concentration (MIC) values of 0.7–2.8 μM, which is up to 10 times lower than that of the reference drug, norfloxacin. Mechanistic studies confirmed that these hybrids disrupt the bacterial membrane. In addition, an increase in intracellular ROS levels was observed for the most active compound. The SHP/QAS hybrids retained high activity against S. aureus ATCC 209P after 17 passages and showed low cytotoxicity (SI = 62–92) and negligible hemolysis. These properties indicate that this approach may offer a useful strategy for developing antibacterial agents with a potentially lower risk of inducing conventional resistance mechanisms. Full article

Leishmaniasis remains a major neglected tropical disease with limited therapeutic options, challenged by drug toxicity and emerging resistance to current treatments like miltefosine. In this study, a virtual library of approximately 150 azole-derived compounds was screened in silico to identify promising thiazole and imidazole scaffolds, leading to the rational design of novel hybrid molecules. Molecular docking against thioredoxin reductase (PDB ID: 4CBQ), a key enzyme in the redox metabolism of Leishmania mexicana, showed improved binding affinity compared to miltefosine, with compound 3f showing the most favourable interaction profile. Among the synthesized series 3a–f, compound 3f (4-NO₂Ph) exhibited the most favourable predicted binding parameters within the series (∆G = −16.08, Ki = 0.0019 nM). Biological evaluation was performed against L. mexicana promastigotes as an early-stage phenotypic screening model to identify active compounds with potential relevance during the initial infective phase, and a markedly improved in vitro inhibitory effect (IC₅₀ = 22.41 µM) compared to miltefosine (IC₅₀ = 132.42 µM), representing a six-fold increase in molar potency. Furthermore, hybrid thiazolyl–imidazole systems (series 3) consistently outperformed single-core analogues, likely due to enhanced molecular planarity and lipophilicity provided by the imine linkage. Cytotoxicity assays in Vero cells revealed a high safety margin for the lead compounds, with compound 3f achieving a Selectivity Index (SI) of around 89, significantly outperforming the reference drug. Acute toxicity studies (LD₅₀) in murine models further confirmed the safety profile, with values exceeding 2000 mg/kg for the most active derivatives. These findings identify thiazolyl–imidazole hybrids as promising early-stage scaffolds for antileishmanial drug discovery, particularly for early infection/prophylactic screening. Full article

Pterostilbene (Pts), a small molecule stilbenoid and a dimethyl analogue of the star molecule resveratrol, exerts significant blood–brain barrier protection on cerebral ischemia-reperfusion injury and has received extensive attention. This study performed structural optimizations on Pts to obtain a series of derivatives and investigated their anti-ischemic activities both in vitro and in vivo, aiming to identify candidates with high safety and improved efficacy compared with Pts. The ADMET method was used to predict the drug-likeness of a series of Pts derivatives, and in vitro MTT cell viability analysis was conducted on neuroblastoma cells (SH-SY5Y) and brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation/reperfusion (OGD/R) injury. On the basis of the cytotoxicity results, four derivatives (NO. 1, NO. 3, NO. 5, and NO. 7) were selected for subsequent in vitro and in vivo biological activities evaluation. These compounds exhibited significantly higher TI values (18.29–30.61) in OGD/R-injured hBMECs compared with Pts (7.63) and effectively suppressed apoptosis, promoted cell migration, and enhanced tube formation capacity. In vivo, NO. 3 (5 mg/kg, ip., 7 d) demonstrated superior efficacy compared to Pts in improving cerebral blood flow, reducing infarction volume, enhancing neurological function, and modulating serum biomarker levels in middle cerebral artery occlusion/reperfusion (MCAO/R) rats, whereas NO. 1 and NO. 7 showed comparable efficacy to Pts. The acute intraperitoneal toxicity of NO. 3 was conducted and showed that the LD₅₀ of NO. 3 was estimated to be more than 300 mg/kg. In this study, the rational design and comprehensive evaluation of Pts derivatives were reported. Compound NO. 3 demonstrated superior pharmacological efficacy to Pts both in vitro and in vivo, and it may be a promising therapeutic candidate for ischemic stroke intervention. Full article

(1) Background: Cinnamaldehyde exhibits a broad spectrum of biological activities, and its α,β-unsaturated aldehyde scaffold serves as a versatile platform for the design of hydrazone derivatives with improved pharmacological properties. (2) Methods: In this study, eight cinnamaldehyde-based hydrazones were synthesized via a one-step condensation reaction between cinnamaldehyde and para-substituted acylhydrazides. Prior to synthesis, an in silico assessment of physicochemical, pharmacokinetic, ADME (absorption, distribution, metabolism, elimination), lead-likeness, and drug-likeness properties was conducted using SwissADME, ACD/Labs v. 9.10, and MDL QSAR v2.2.0.0.446 software. Structural characterization by IR, ¹H NMR, ¹³C NMR, and HR ESI–MS confirmed successful formation of the hydrazone linkage. Cytotoxic activity was evaluated using the MTT assay against selected cancer cell lines. (3) Results: All compounds exhibited favorable lead-like characteristics, including suitable molecular weight, moderate lipophilicity, and acceptable predicted ADME profiles. Biological evaluation revealed moderate, structure-dependent antiproliferative activity with clear cell line selectivity. Among the series, compound CA8 showed the most promising profile, displaying the highest cytotoxic activity against T-cell leukemia KE-37 cells (IC₅₀ = 20.3 ± 2.8 μM), comparable to reference drug melphalan (IC₅₀ = 21.40 ± 3.9 μM), and the highest selectivity index (≥19.7). Structure–activity analysis suggests that an amino substituent enhances both potency and selectivity. (4) Conclusions: Overall, these findings identify cinnamaldehyde hydrazones as a promising scaffold for anticancer drug development and provide a strong basis for further structural optimization. Full article

Background and Objectives: Neuroblastoma represents the most common extracranial solid tumor in childhood and is associated with a poor prognosis in high-risk cases. Amygdalin, a naturally occurring cyanogenic glycoside, has been reported to exhibit anti-tumor properties in various cancer models; however, its effects on neuroblastoma cells remain insufficiently characterized. The present study was conducted with the objective of investigating the effects of amygdalin on cell proliferation, apoptosis, and invasion in SH-SY5Y neuroblastoma cells in vitro. Materials and Methods: The SH-SY5Y neuroblastoma cells were cultivated under the optimal conditions for their growth. The cytotoxic effect of amygdalin was determined using the CCK8 assay, which is dose- and time-dependent. Total RNA isolation was performed using Trizol. Subsequently, a process of cDNA synthesis was initiated. The real-time PCR method was utilized to ascertain alterations in the expression levels of mRNA molecules associated with apoptosis, namely Bax, Bcl2, caspase-3, caspase-7, caspase-8, caspase-9, caspase-10, NFkB, and invasion-related genes MMP2, MMP9, TIMP1, and TIMP3. Furthermore, alterations in NFkB levels were examined through the utilization of the ELISA method. Results: The IC50 value of amygdalin in SH-SY5Y cells was determined to be 112.7 µM at 24 h. Amygdalin demonstrated a dose-dependent cytotoxic effect on neuroblastoma cells. Furthermore, the study revealed that the drug induced apoptosis through the upregulation of BAX and BID, and the downregulation of BCL-2 and NF-κB. This process led to a reduction in cell proliferation. Furthermore, the study demonstrated an anti-invasive effect through the downregulation of MMP9 and the upregulation of TIMP1 and TIMP3. In addition, a substantial decrease in NF-κB protein concentration was observed. Conclusions: These findings demonstrate that amygdalin exerts anti-proliferative, pro-apoptotic, and anti-invasive effects in SH-SY5Y neuroblastoma cells in vitro. Amygdalin may represent a promising natural compound for further investigation as a potential therapeutic agent in neuroblastoma. Full article