Background: Nowadays, scientists are trying to design a developed carrier for delivering drugs specifically to cancerous cells. This study aimed to design the poly (acrylamide-maleic anhydride)/(FA & TPGS) coated nanoliposome (P(AAm-MA)/(FA & TPGS) NL) as an FA-modified targeted drug delivery system. Methods: The P(AAm-MA)/(FA & TPGS) copolymer was synthesized via free radical polymerization of AAm and MA, followed by chemical grafting of FA-NH2 and TPGS-SS-NH2. Also, the nanoliposome (NL) was prepared by the thin lipid film hydration method and the Doxorubicin (DOX) was encapsulated into the core of nanoliposome during lipid bilayer formation. After that, the copolymer was used to coat the NL in order to prepare P(AAm-MA)/ (FA & TPGS) NL. The cytotoxicity of DOX-loaded P(AAm-MA)/(FA & TPGS) NL, pure DOX and blank P(AAm-MA)/(FA & TPGS) NL against MCF-7 were measured by MTT assay. The intracellular uptake of free DOX and DOX-loaded P(AAm-MA)/(FA & TPGS) NL against MCF-7 was studied using a fluorescence microscope. Results: The P(AAm-MA)/(FA & TPGS) copolymer was initially investigated by FT-IR, then the TEM analysis of P(AAm-MA)/(FA & TPGS) NL was performed, and showed that the copolymer formed a thin layer around liposomal vesicles. Also, the TEM and DLS results confirmed the preparation of P(AAm-MA)/(FA & TPGS) NL with less than 100 nm diameter. The zeta potential results confirmed the coating of NL with copolymer by electrostatic interactions. The DOXloaded P(AAm-MA)/(FA & TPGS) NL exhibited enhanced cellular uptake through FA-mediated endocytosis. The efficiency of DOX-loaded P(AAm-MA)/(FA & TPGS) NL against MCF-7 was verified by MTT, and exhibited higher cytotoxicity of the DOX-loaded P(AAm-MA)/(FA & TPGS) NL compared to pure DOX. Conclusion: Overall, the P(AAm-MA)/(FA & TPGS) NL controlled MCF-7 cells' growth because of its enhanced cellular uptake via FA-mediated endocytosis. Thus, the prepared nanoliposome carrier can be a suitable choice for inhibiting the growth of cancer cells.
Background: Brain drug delivery is of paramount significance in CNS-related diseases as blood brain barrier (BBB) permeability is not feasible for many pharmaceutical agents. The purpose of this study was to identify peptide sequences with specific translocation property into brain via intranasal route using in vivo phage display method to be used as CNS drug delivery carriers. Methods: To screen peptides with nose-to-brain translocation capability, a 12-mer peptide library displayed on M13 bacteriophage was intranasally administered to anesthetized mice with subsequent recovery of the phage particles from the brain. The identified peptide sequences were analyzed using bioinformatics tools. Results: The results showed that intranasal transport of phage particles to the brain is independence of displayed peptide sequences due to random distribution of residues in different positions of isolated peptides. Nanoscale feature of bacteriophage particles may be responsible for nose-to-brain translocation through olfactory epithelium. Conclusion: Taken together, the results open a route for designing phage-guided therapeutic systems as nanocarriers useful in intranasal brain targeting drug delivery.
Background: Botox’s therapeutic applications are limited by its instability and uncontrolled diffusion into extramuscular tissues. This study aims to develop a polyethylene glycol-based formulation by conjugating Botox to a second-generation anionic linear-globular dendrimer (G2-ALGDs) and evaluate its colloidal stability and muscle localization using technetium-99m radioimaging. Methods: G2-ALGDs were synthesized via N,N′-dicyclohexylcarbodiimide catalysis and conjugated with Botox (D-BTX) using EDC/DCC coupling. Characterization was done by DLS, FTIR, AFM, TEM, and FE-SEM. Stability at 4 °C was monitored for six months using DLS and TEM. Cytocompatibility was assessed by MTT assay in HFF2 cells. D-BTX was radiolabeled with technetium-99m to study purity, stability, and in vivo biodistribution using RT-LC and SPECT imaging. Results: Botox conjugation increased the particle size from 111.6±16.9 nm to 160.0±3.1 nm and shifted the zeta potential from –25.2±1.63 mV to+17.16±1.24 mV. FTIR confirmed amide bond formation at 1649 cm⁻¹. D-BTX was much less cytotoxic than free Botox at 0.001 ng/mL (p=0.0013), but no difference was observed at higher concentrations. The formulation exhibited physical stability for six months at 4°C. The radiolabeled formulation was up to 90.85% pure and remained stable for 24 h. SPECT imaging revealed improved localization of D-BTX within the muscle. After 12 h, D-BTX exhibited maximum signal intensity with minimal dispersion, indicative of controlled diffusion at the injection site. Conclusion: This PEGylated dendrimer-Botox nanoconjugate provides a stable, muscle-targeting, and imageable platform, which surmounts some of the main drawbacks in current clinical applications.
Background: Ivermectin (IVM) is a broad-spectrum antiparasitic drug used in humans and animals to treat infections like scabies, river blindness, and various worms. Derived from avermectin via fermentation, IVM contains impurities and degradation products. During pandemics like COVID-19, demand for IVM formulations surges, requiring specialized manufacturing. Classified as a Biopharmaceutics Class II drug, IVM has high permeability but low solubility, leading to poor dissolution and variable absorption, impacting efficacy. Enhancing solubility can improve bioavailability and aid in purification, crystallization, and analysis. Thus, optimizing IVM formulations is crucial for better therapeutic outcomes. Methods: This work investigated the IVM solubility in binary mixtures of ethylene glycol and water, at a temperature range of 298.2 K to 313.2 K. A laser-based robotic system was employed to measure the solubility data. The generated solubility values were presented utilizing various thermodynamic models, such as the van't Hoff, mixture response surface, Jouyban-Acree, Jouyban-Acree-van't Hoff, and modified Wilson models. Several thermodynamic factors, including Delta G degrees, Delta H degrees, and Delta S degrees were also computed according to the experimental findings. Results: The results showed that in the EG -rich mixtures and proportional to temperature, the IVM solubility significantly increased. The mathematical models effectively estimated IVM solubility in binary solvents, with MRD% ranging from 5.7 to 13.7. Thermodynamic analysis revealed non-spontaneous dissolution, and endothermic reaction for IVM dissolution in the investigated mixtures. Conclusion: These properties offered valuable insights into the energetic characteristics of the dissolution process and computed utilizing the Gibbs and van't Hoff equations.
Background: Bilastine is a second-generation antihistamine belonging to poorly soluble, highly permeable drug class. This resulted in low and variable oral bioavailability. Being antihistaminic, its combination with caffeine is possible. Accordingly, the aim was to research bilastine/caffeine solid dispersion on the dissolution rate and oral bioavailability of bilastine. Methods: Ethanol-aided kneading of mixtures of bilastine and caffeine at molar ratios of 1:1 (C1), 1:2 (C2) and 1:3 (C3) was achieved. The kneading process continued till complete vaporization of ethanol and was repeated four times. During the last co-grinding step, an amount of Avicel equivalent to bilastine weight was added to obtain flowable mixtures. The resultant systems were characterized by FTIR, DSC, PXRD and in-vitro dissolution. The optimum formulation was assessed in-vivo for antihistaminic effect using Carrageenan induced paw edema. Results: Instrumental analysis indicated molecular dispersion of bilastine in caffeine matrix or transformation into amorphous state. The different formulations exhibited enhanced dissolution parameters compared to native bilastine. Pure bilastine powder exhibited dissolution efficiency (%DE) of 54.24% with only 10.96% of bilastine dose was dissolved in first five minutes (Q5). Co grinding of bilastine and caffeine increased Q5 to 33.64%, 54.80% and 63.94 % for C1, C2 and C3, respectively. Besides, % DE values reached 74.80%, 83.22% and 78.88% for them, respectively. Augmented dissolution improved bilastine antihistaminic efficacy of C2 reflecting better bioavailability. This was manifested as significant reduction in the area under edema formation in case of C2 compared to drug suspension, untreated group, the physical mixture, and the physical mixture without bilastine (Avicel plus caffeine). Conclusion: The study introduced bilastine-caffeine solid dispersion as simple tool to hasten bilastine dissolution and efficacy.
Background: Cubosomes are nanostructured lipid carriers with a bicontinuous cubic phase that can encapsulate both hydrophilic and lipophilic drugs, making them promising systems for transdermal delivery. Tizanidine (TZN), a centrally acting α2-adrenergic agonist, exhibits limited oral bioavailability due to extensive first-pass metabolism. TZN nanocubosomal gel (TNCUBs-gel) was developed and in vitro release, ex vivo skin permeation, and in vivo pharmacokinetics were evaluated in comparison with its oral solution. Methods: TZN-loaded cubosomal dispersion was used as the base system and incorporated into Carbopol 934 gels (1, 1.5 and 2% w/w) to prepare TNCUBs (g1-g3). The formulations were screened for pH, viscosity, and texture, and the 1.5% formulation (TNCUBs-g2) was selected for further studies. In vitro release was evaluated over 24 h, ex vivo permeation across rat skin was investigated using Franz diffusion cells, and in vivo pharmacokinetic studies were conducted in adult male Wistar rats to compare the transdermal TNCUBs-gel with an oral TZN solution. Plasma TZN concentrations were quantified using a validated HPLC-UV method. Results: TNCUBs-g2 released 59.7±1.9% of TZN over 24 h. Ex vivo, TNCUBs-g2 exhibited a fourfold higher flux (32.3 µg cm⁻² h⁻¹) than the plain solution. In vivo, the transdermal formulation achieved substantially greater systemic exposure with AUC₀–₂₄=1403.19±42.1 ng·h/mL versus 455.05±9.5 ng·h/mL for oral dosing (P<0.001), indicating sustained absorption and enhanced bioavailability. Conclusion: The TNCUBs-gel represents a stable, controlled-release transdermal platform that markedly enhances skin permeation and systemic exposure compared with oral administration, supporting its therapeutic potential.
Background: The therapeutic potential of polyphenols like resveratrol (Res) and gallic acid (GA) in wound healing is limited by their poor aqueous solubility and chemical instability. This study aimed to develop and characterize a novel hydrogel-based drug delivery system to overcome these limitations and achieve synergistic therapeutic effects. Methods: The strategy involved two key components, a Res/GA inclusion complex (Res/GA-IC) prepared using hydroxypropyl-(3-cyclodextrin (HP-(3-CD) to enhance polyphenol solubility and stability, and a dual-crosslinked carboxymethyl cellulose-poly(vinyl alcohol) (CMC-PVA) hydrogel formulated as a delivery vehicle for the IC. The properties of the Res/GA-IC and the final hydrogel patch were characterized. Results: Formulation of the Res/GA-IC resulted in a remarkable increase in the aqueous solubility of Res. The Res/GA combination showed strong synergistic antioxidant activity (CI < 0.3), and the Res/GA-IC demonstrated enhanced antibacterial efficacy against Staphylococcus aureus. The CMC-PVA hydrogel dressing incorporating the IC showed favorable physicochemical properties, including appropriate swelling capacity, structural integrity, and sustained release characteristics for both active agents. Crucially, the final formulation was highly biocompatible with human fibroblast cells. Conclusion: This work presented a successful formulation strategy for the co-delivery of poorly soluble synergistic polyphenols. The developed hydrogel dressing represents a promising therapeutic platform for advanced wound management by effectively addressing key challenges of oxidative stress and bacterial infection.
Background: Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation and oxidative stress, primarily driven by cigarette smoke (CS) exposure. While high-intensity interval training (HIIT) and polyphenol-rich supplements such as Yerba Mate (YM) have demonstrated anti-inflammatory and antioxidant properties, the combined effects of HIIT with a niosomal YM formulation (Nio-YM) remain unexplored. This study aimed to investigate the individual and combined effects of HIIT, YM, and Nio-YM on inflammatory cytokines (IL-6, IL-10, TNF-alpha), oxidative stress markers (MDA, TAC), and physical performance in a rat model of CS-induced lung injury. Methods: Male rats were randomly allocated into seven groups: control (CON), CS, CS + Vehicle (Veh), CS + YM, CS +Nio-YM, CS + HIIT, and CS + HIIT +Nio-YM. The interventions consisted of an 8 week HIIT protocol, Yerba Mate (YM) extract (0.5 mg/kg, orally), and its niosomal formulation (orally). Lung cytokines (IL-6, IL-10, TNF-alpha), oxidative stress markers (MDA, TAC), and exercise performance indices (exhaustion running time, maximum running speed) were evaluated. Results: CS exposure markedly increased IL-6, TNF-alpha, and MDA, while reducing IL-10 and TAC, indicating an inflammatory and oxidative burden. All interventions significantly reversed these alterations. TAC levels were higher in the HIIT and YM groups compared with other treatments, suggesting a stronger enhancement of antioxidant defenses. However, no significant synergistic effects were observed in the HIIT +Nio-YM group. Additionally, the 8-week HIIT protocol significantly improved exhaustion running time and maximum running speed in CS-exposed rats. Conclusion: HIIT, YM, and Nio-YM attenuated CS-induced inflammation and oxidative stress while improving exercise performance. Although the combined intervention did not show additive effects, both HIIT and YM demonstrated robust protective outcomes. These findings support the potential of combining structured exercise with polyphenol-based supplementation as an effective non-pharmacological strategy for mitigating COPD progression.
Background: Breast cancer (BC) remains the leading cause of cancer-related mortality among women globally. Despite significant advances in diagnosis and treatment, the molecular mechanisms driving breast tumorigenesis are not yet fully elucidated. This study aimed to identify key genes and signaling pathways associated with BC pathogenesis and prognosis through comprehensive bioinformatic analysis. Methods: In this study, gene expression data from the GSE124646 dataset were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified based on the criteria of dlog2 fold changed > 1.5 and P value < 0.01. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were conducted. In addition, protein-protein interaction (PPI) network was constructed using STRING database and visualized using Cytoscape. Hub genes were identified based on network topology (degree >= 7; betweenness centrality between 0.005 and 1). Further validation was performed using the GEPIA web tool and Kaplan-Meier survival analysis. Results: A total of 923 DEGs were identified, comprising 645 upregulated and 278 downregulated genes. Enrichment analysis revealed that these genes were predominantly involved in extracellular matrix (ECM) organization and localized within collagen-containing ECM components. Molecular function analysis indicated significant enrichment in glycosaminoglycan binding. KEGG pathway analysis highlighted the PI3K-Akt signaling pathway as a major pathway implicated in BC. 73 hub genes were identified and incorporated into the PPI network. Survival analysis demonstrated that elevated expression of several hub genes was significantly associated with poor prognosis. GEPIA analysis confirmed aberrant expression of these genes in BC tissues compared to normal controls. Conclusion: These findings enhance our understanding of the molecular underpinnings of breast cancer and highlight potential diagnostic biomarkers and therapeutic targets. Furthermore, this study identifies a subset of previously under-characterized genes, which may contribute to refining the molecular taxonomy and treatment strategies of BC.
Background: This study aimed to investigate the impact of sodium lauryl sulfate (SLS) and sodium lauryl ether sulfate (SLES), two anionic surfactants, on human hair at different pH levels and temperatures, using the Lowry method and Zein tests to assess hair damage and to check the Zein test's relevance to hair protein loss data. Methods: Hair bundles were placed in solutions of SLS and SLES at varying concentrations (5, 10, 20, and 30% w/v), pH levels (5, 7, and 8), temperatures (37 degrees C and 42 degrees C), and durations (10 minutes and 24 hours). Then, the samples were analyzed for absorption at 750 nm using a UV-visible spectrophotometer. The results were compared with the Zein test. Results: With a 10-minute exposure duration, elevating the concentrations of SLS and SLES from 5% to 30% resulted in a threefold increase in protein loss for SLS, compared by a sixfold increase for SLES. While the elevation of pH led to a rise in protein loss for both surfactants, the extent of this increase was more pronounced in SLS than in SLES. An increase of 5 degrees C in temperature during exposure to the surfactants nearly doubled the protein loss. Long exposure time to SLS exhibited minimal impact on the extent of protein loss. In contrast, prolonged exposure to SLES significantly increased protein loss. A good correlation was observed between the results of the Lowry and the Zein tests. Conclusion: The research provided important information on factors like pH, concentration, and exposure time that can impact protein loss results. The findings suggest that hair care products should be formulated with lower concentrations of these surfactants at pH levels of 5-7 to minimize protein loss. Manufacturers can use Zein test and the Lowry method in parallel to evaluate hair damage in a comparative manner.
Background: Mild Cognitive Impairment (MCI) is considered a cognitive impairment more than expected for an individual’s age and education without interference with daily life. However, current treatment options for MCI have limited curative effects and mainly focus on symptomatic management. In this regard, herbal medicines have been the focus of attention because they are relatively inexpensive and perceived to carry lower risks. This research was conducted regarding the effects of Zintoma® capsules, containing ginger, on MCI patients. Methods: After obtaining ethics committee approval (Birjand University of Medical Sciences, IR.BUMS.REC.1399.502), and receiving the IRCT code (IRCT20201228049868N2), this double-blind, randomized clinical trial was conducted with 60 patients diagnosed with MCI diagnosis and aged 18 years or older. The eligible participants were assigned using a randomized block design (blocks of four) to either the Zintoma® group that received three capsules (250 mg each) once daily for two months or the placebo group that consumed three capsules (250 mg each) once daily for two months. Assessment of the patients was performed at the baseline and then every four weeks by MMSE and CDR criteria. Results: The mean age of patients was 51.73±6.53 years, with 30 male patients accounting for 50%. There were no statistical differences in demographic characteristics between the two groups. The results indicated that after the consumption of Zintoma® capsules, CDR and MMSE scores improved significantly in the course of the treatment, leading to improved memory in patients at 4 and 8 weeks (P<0.001). The incidence of side effects was not statistically significantly different between the two groups. Conclusions: The study thereby concludes that the administration of Zintoma® capsules may result in a positive impact on patients with MCI, leading to a clinical improvement of memory. However, larger clinical trials are needed to confirm these findings.
Background: 5-Fluorouracil (5-FU) is commonly used to inhibit gastric cancer (GC) cell growth, but its clinical effectiveness is frequently limited by chemoresistance. Dicyclomine (DIC), an anticholinergic agent, has been suggested to enhance the therapeutic effect of 5-FU in cancer treatment. Objectives: This study aimed to investigate the effects of 5-FU, DIC, and their combination on AGS cell viability and the expression of SNAIL2 and P53. Methods: AGS cells were cultured in Dulbecco's Modified Eagle Medium/F12 supplemented with 10% fetal bovine serum (FBS). Cell viability was assessed using the 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The mRNA expression levels of P53 and SNAIL2 were analyzed by quantitative real-time PCR (qRT-PCR). Drug synergism was evaluated using the CompuSyn software. Network pharmacology was employed to investigate the potential relationship between DIC and the expression of P53 and SNAIL2 genes. Results: The IC50 values for 5-FU and DIC were 4 & micro;g/mL and 800 & micro;g/mL, respectively. In AGS cells, all treatments significantly upregulated P53 expression (5-FU: P< 0.01; DIC: P< 0.001; Combination: P< 0.0001). While 5-FU (P < 0.01) or DIC (P < 0.0001) alone increased SNAIL2 expression, their combination significantly reduced it (P< 0.05). CompuSyn software confirmed a synergistic interaction. KEGG pathway analysis revealed 38 enriched pathways, with the adherens junction pathway, highlighted due to its potential role in SRC protein-mediated downregulation of SNAIL gene expression. Conclusion: These findings indicate that the combination of 5-FU and DIC synergistically exerts significant anticancer effects by upregulating P53 and downregulating SNAIL2 expression, representing a promising strategy for optimizing GC management.
Background: Daunorubicin, an anthracycline antibiotic widely used in chemotherapy, is limited due to its dose-dependent cardiotoxicity. Omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) provide cardioprotective benefits through reducing oxidative damage, suppressing inflammatory markers and enhancing antioxidant defenses. TND1128, a novel 5-deazaflavin derivative with mitochondrial-targeted redox activity, has been studied in hepatic and neuronal oxidative stress models, but its cardioprotective potential remains unexplored. This study aimed to evaluate the efficacy of Omega-3 and TND1128 in preventing daunorubicin-induced cardiotoxicity. Methods: Thirty-six male Wistar rats were randomized into six groups: Group Ӏ received corn oil; Group ӀӀ received daunorubicin (12 mg/kg i.p., last 3 days; cumulative dose 36 mg/kg); Group III received omega-3 (600 mg/kg/day, orally, 14 days); Group ӀV received omega-3 (600 mg/kg/day, by oral gavage,14 days)+daunorubicin (12 mg/kg i.p., last 3 days); Group V received TND1128 (10 mg/kg/day, by oral gavage, 14 days), and group VI received TND1128 (10 mg/kg/day, by oral gavage,14 days)+daunorubicin (12 mg/kg i.p., last 3 days). Cardiac injury indicators, oxidative stress markers, inflammation mediators, apoptotic signaling components (caspase-3), and histopathological analysis were assessed. Results: Both interventions significantly attenuated daunorubicin-induced biochemical, molecular, and histological alterations (P<0.01). TND1128 showed greater efficacy in reducing apoptosis and inflammation compared to omega-3 fatty acids, highlighting its potential as an adjunct therapy in anthracycline-based regimens. Conclusion: Omega-3 fatty acids and TND1128 significantly protected against daunorubicin-induced cardiotoxicity by improving oxidative stress, inflammation, apoptosis, and myocardial integrity. TND1128 provided superior protection, supporting its potential as an adjunct therapeutic strategy in anthracycline chemotherapies.
Background: Obesity, a multifaceted metabolic condition, is associated with oxidative stress and disrupted redox homeostasis, leading to ferroptosis and metabolic dysfunction. Liraglutide, a well-known glucagon-like peptide-1 (GLP-1) receptor agonist, is used in the treatment of obesity. This study aimed to examine the modulatory effects of liraglutide on oxidative stress and ferroptosis-related indicators in obese rats induced by high-fat diet (HFD). Methods: Thirty-five male Wistar rats were randomly divided into five groups: a control group, an HFD-induced obesity group, and three liraglutide treatment groups (100, 200, and 400 μg/kg/day). Following a 4-week induction of HFD, liraglutide was administered subcutaneously for 28 days. Redox and ferroptosis changes were assessed by measuring serum iron, TfR-1, malondialdehyde (MDA), and superoxide dismutase (SOD), along with gene expression of SLC7A11 and the immunohistochemical expression of heme oxygenase-1 (HO-1) and glutathione peroxidase 4 (GPX4) in hepatic tissues. Results: HFD-induced obesity significantly reduced the expression of antioxidant and ferroptosis-regulatory markers. Liraglutide treatment, particularly at high doses, significantly reversed these effects by upregulating SLC7A11 gene expression and enhancing HO-1, and GPX4 protein expression in a dose-dependent manner. Conclusion: These findings suggest that liraglutide restores antioxidant capacity and inhibits ferroptosis through activation of the SLC7A11/HO-1/GPX4 axis. Beyond its metabolic benefits, liraglutide exerted cytoprotective effects, highlighting its potential therapeutic role in obesity-associated oxidative stress and ferroptosis injury.
Background: Solubility of drugs is an important issue in pharmaceutical industry and the solubility of polymorphs play a critical role in dealing with the solubility issue. This work summerizes the effects of crystal structure on drug's solubility with special focus on the modeling approaches. Methods: The reported solubility data of polymorphs of drugs (i.e. buspirone HCl, clopidogrel hydrogen sulfate, dabigatran exetilate mesylate, flufenamic acid, glycine, indomethacin, mefenamic acid and sofosbuvir) in mono-/mixed-solvent systems were collected from the literature. The data and modeling results were briefly reviewed and the solubility ratios of the polymorphs were calculated. The applicability of the proposed cosolvency models to simulate the solubility of different polymorphs of a solute in mono-or mixed-solvents at various temperatures were shown employing the collected data. The accuracy of the models was assessed by computing the mean percentage deviations (MPDs) of the simulated and measured solubilities. Results: The overall MPD for correlated solubility data of polymorphs of drugs in mono-solvents at various temperatures using a correlative multi-parameter model was 8.9% and that for mixed-solvents using the Jouyban-Acree model was 6.7%. The results of predictions in mixed-solvents provided acceptable errors (overall MPD of 16.6%) and could be recommended for practical applications in the industry. Conclusion: The provided computational methods provided satisfactory results and could be considered as practical solution in the industrial applications.
Background: Indonesia, an archipelagic nation, is home to the second-highest biodiversity in the world, which includes Bajur (Pterospermum javanicum Jungh.) leaves, which has been used to treat lipid metabolic disorders. To the best of our knowledge, there is no report on P. javanicum Jungh regarding its antihyperlipidemic potency and its chemical constituents. This study aims to evaluate the antihyperlipidemic activity of the P. javanicum methanolic leaves extract, its fractions and its constituents. Methods: The P. javanicum leaves extraction was performed using maceration and liquid-liquid extraction method. The major constituent of the ethyl acetate fraction was isolated using column chromatography and further purification using high performance liquid chromatography (HPLC) and its structure was elucidated through nuclear magnetic resonance (NMR). The antihyperlipidemic activities of isolated compounds were evaluated using computational studies by mean binding affinity with lipase (1LPB) enzymes, in which their potency was compared against the standard drugs, orlistat. Antihyperlipidemic activity of P. javanicum extracts were screened using lipase enzyme inhibition assay. The antioxidant activity was evaluated using 2,2-Diphenyl-1-picrylhydrazyl (DPPH) scavenging reaction. Results: The in vitro study showed the ethyl acetate fraction significantly inhibited the lipase enzyme and free radicals with an IC50 value of 1.84±0.09 µg/mL and 76.67±1.37 µg/mL, respectively. Two flavonoids, kaempferol-3-O-rhamnoside 1 and quercetin-3-O-rhamnoside 2 were successfully isolated and elucidated with stronger binding affinity with 1LPB enzymes than orlistat. Conclusion: The study confirmed P. javanicum leaves potency as source for antihyperlipidemic and antioxidant agents.
Background: Inhibition of cancer cell migration is an appropriate strategy for the prevention of metastasis. The purpose of this study was to identify new carbonyl thioureas as inhibitors of gastric cancer cell migration. Methods: N1-(morpholin-4-yl ethyl)/phenyl/aralkyl-N3-(thiophene-2-carbonyl)/benzoyl thioureas (1-12) were synthesized by one-pot two step reaction and assessed for their effect on growth and migration of human adeno gastric stomach (AGS) cell lines through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and wound-healing assays. Ras homolog family member A (RhoA) is a guanosine tri-phosphatase (GTPase) oncogenic target with crucial role in gastric cell migration and accordingly molecular docking and molecular dynamics (MD) simulations were performed on RhoA by AutoDock4 and GROningen MAchine for chemical simulations (GROMACS5) software. Drug-likeness scores and pharmacokinetics properties were calculated by MolSoft tool through SwissADME (ADME: absorption, Distribution, Metabolism and Excretion) online server. Results: All of the compounds relatively inhibited wound-healing process after 24 h, whereas compound 4 exhibited comparable anti-migratory activity to cis-platin. Compound 4 might exhibit true migrastatic effect (6.25 μg/mL) without significant cytotoxicity. SwissADME data were indicative of high gastrointestinal (GI) absorption and with the exception of compounds 7 and 9, all the compounds had lower risk of producing efflux-based resistance. Docking and MD simulations provided stable binding model for top-scored derivative (compound 4) inside RhoA binding site near to the GTP-binding pocket. All the structural indices were converged in the MD simulations and free energy calculations showed appropriate accommodation inside the RhoA binding site. Bind trajectory analysis revealed no stable intermolecular H-bonds within simulation time and the complex was majorly stabilized through hydrophobic contacts. Conclusion: The results of the current study suggested that compound 4 may be an appropriate candidate for further development into selective small molecule GTPase inhibitors against gastric cancer metastasis.
Background: Despite the progress in the management of late-onset sepsis (LOS), it is the leading cause of mortality in preterm infants worldwide. Pentoxifylline is a methylxanthine with well-documented immunomodulatory properties, which may be an important approach to treating LOS.This study aimed to evaluate the efficacy and safety of adding oral pentoxifylline standard care among preterm neonates with LOS. Methods: In this trial, 47 preterm neonates with a confirmed diagnosis of LOS were allocated to either receive Pentoxifylline 10 mg/kg three times a day orally plus standard care (n=23) or the standard care alone for 6 days (n=24) using the block randomization method. The primary outcomes were the duration of C-reactive protein (CRP) negativity, duration of supplemental oxygen therapy, hospitalization and mortality rate. Secondary outcomes included the assessment of any adverse events that may have occurred during the study. Continuous data were analyzed using the independent t-test or Mann–Whitney U test. Chi-square and/or Fisher’s exact tests are used for categorical variables. The logistic regression analysis was also used for comparing mortality after adjusting for covariates. Results: The demographic characteristics, mothers/infants-related risk factors, use of antenatal steroids, neonatal resuscitation, antibiotic regimen, and surfactant administration were statistically similar between the intervention and control groups; however, respiratory support significantly differed. After adjusting for respiratory support, there was no significant difference regarding the duration of hospitalization (P=0.56), CRP negativity (P=0.69), supplemental oxygen therapy (P=0.94), and mortality rate (P=0.5) between the study groups. Conclusion: Adding oral pentoxifylline to standard care had no significant benefits on clinical and paraclinical outcomes in preterm neonates with LOS. Further clinical trials are needed to test the study hypothesis.
Background: Aging is associated with a wide range of cognitive impairments that affect the quality of life in the elderly. This study aimed to assess the neuroprotective properties of the hydro-alcoholic extract of Melissa officinalis L. (HAEMO) on cognitive impairment mediated by the D-galactose/AlCl₃-induced accelerated aging model. Methods: The C57BL/6 mice were allocated into young and aged control groups, and three aged groups received different doses of HAEMO for 60 days. The performance of mice was assessed using the Lashley III maze and the novel object recognition test to assess cognitive function. Hippocampal tissue was examined not only for oxidative stress indicators (TAC, MDA, GPx and SOD) but also used for estimations of Sirt-1, Nrf2, NF-кB, IL-6, and TNF-α proteins. Results: The results indicated improved spatial and recognition memories in the HAEMO-received aged animals. The behavioral advantages were probably linked to diminished lipid peroxidation, increased antioxidant enzyme activities, and enhancement of the hippocampal Sirt-1/Nrf2 pathway. Moreover, the HAEMO regimen reduced inflammatory markers (NF-κB, TNF-α, and IL-6) in the hippocampus. Conclusion: HAEMO exerts a modulatory effect on the hippocampal Sirt-1/Nrf2/NF-κB pathway, offering a neuroprotective approach against progressive oxidative stress and neuroinflammation that develop with aging. Additional research is necessary to completely understand the therapeutic potential of HAEMO in the preservation of cognition during aging.
