Bisphenol A promotes cell death in healthy respiratory system cells through inhibition of cell proliferation and induction of G2/M cell cycle arrest.

Bisphenol A (BPA) is a substance that can harm the environment and human health by interfering with the normal functioning of the body's hormonal system. It is commonly found in various plastic-based products such as cosmetics, canned foods, beverage containers, and medical equipment and as well as it can also be absorbed by inhalation. There have been limited studies on the effects of BPA on lung fibroblasts, and it is still unclear how high levels of BPA can impact respiratory system cells, particularly the lungs and trachea. In this research, we aimed to investigate the cell cycle disruption potential of BPA on respiratory system cells by examining healthy trachea and lung cells together for the first time. The findings indicated that BPA exposure can alter the healthy cells' morphology, leading to reduced cellular viability that has been assessed by MTT and SRB assays. BPA treatment was able to activate caspase3 as expected, which could cause apoptosis in treated cells. Although the highest dose of BPA did not increase the apoptotic rate of rat trachea cells, it remarkably caused them to become necrotic (52.12%). In addition to quantifying the induction of apoptosis and necrosis by BPA, cell cycle profiles were also determined using flow cytometry. Thereby, BPA treatment unexpectedly inhibited the cell cycle's progression by causing G2/M cell cycle arrest in both lung and tracheal cells, which hindered cell proliferation. The findings of the study suggested that exposure to BPA could lead to serious respiratory problems, even respiratory tract cancers via alterations in the cell cycle.

Hispidulin exerts a protective effect against oleic acid induced-ARDS in the rat via inhibition of ACE activity and MAPK pathway.

This study investigates the protective role of Hispidulin on acute respiratory distress syndrome (ARDS) in rats. Rats were divided into three groups: control, ARDS, ARDS+ Hispidulin. The ARDS models were established by injecting rats with oleic acid. Hispidulin (100 mg/kg) was injected i.p. an hour before ARDS. Myeloperoxidase (MPO), Interleukin-8 (IL-8), Mitogen-activated protein kinases (MAPK), Lipid Peroxidation (LPO), Superoxide Dismutase (SOD), Glutathione (GSH), and Angiotensin-converting enzyme (ACE) were determined by ELISA. Tumor necrosis factor-alpha (TNF-α) expression was described by RT-qPCR. Caspase-3 immunostaining was performed to evaluate apoptosis. Compared with the model group, a significant decrease was observed in the MPO, IL-8, MAPK, ACE, LPO levels, and TNF-α expression in the ARDS+ Hispidulin group. Moreover, reduced caspase-3 immunoreactivity and activity of ACE were detected in the Hispidulin+ARDS group. The protective effect of Hispidulin treatment may act through inhibition of the ACE activity and then regulation of inflammatory cytokine level and alteration of apoptosis.

Evaluation of cytotoxic and apoptotic effects of the extracts and phenolic compounds of Astragalus globosus Vahl and Astragalus breviflorus DC.

Astragalus L. is a genus member of the Fabaceae family, representing about 3,000 species all over the world and 380 species in Turkey. Astragalus species have been used in traditional medicine for many years. Astragalus globosus Vahl, known as "top geven", is a dwarf, scapose, perennial herb, Astragalus breviflorus DC., known as "yünlü geven", is an extremely spiny dwarf shrub. These endemic species grow in the Turkish cities of Erzurum, Kars, and Van. This is the first phytochemical and cytotoxic investigation of Astragalus globosus Vahl and Astragalus breviflorus DC. The main extracts and sub-fractions from the plants were evaluated for in vitro cytotoxic and apoptotic activities. The IC50 values of dichloromethane, n-butanol, and water extracts of the aerial parts of A. globosus against the MCF-7 cell line were determined as 28.39, 868.60, and 1753.00 µg/mL. The values for the MDA-MB-231 cell line were 264.00, 620.30, and 1300.50 µg/mL, respectively. From A. globosus, the following were isolated: a flavone glycoside, diosmetin-7-O-rutinoside (1); and two flavonol glycosides, isorhamnetin-3-O-rutinoside (2) and quercetin-3-O-galactoside (3). From A. breviflorus, two phenolic acids, caffeic acid (4) and chlorogenic acid (5), and a flavan-3-ol, catechin (6), were isolated. Diosmetin-7-O-rutinoside was isolated from Astragalus species for the first time and showed the highest cytotoxic activities on the MCF-7 and MDA-MB-231 breast cancer cell lines with IC50 values of 13.65 and 12.89 µg/mL, respectively. Moreover, we observed that diosmin exerts cytotoxic effects by causing cell necrosis.

Combining vancomycin-modified gold nanorod arrays and colloidal nanoparticles as a sandwich model for the discrimination of Gram-positive bacteria and their detection via surface-enhanced Raman spectroscopy (SERS).

This study reports the development of a highly sensitive antibiotic-based discrimination and sensor platform for the detection of Gram-positive bacteria through surface-enhanced Raman spectroscopy (SERS). Herein, a combination of gold nanorod arrays (GNAs) and colloidal gold nanoparticles (AuNPs) was used as a SERS platform. To specifically capture Gram-positive bacteria, both GNAs and AuNPs were functionalized with thiol-modified vancomycin (HS-Van) molecules. Three different strains of bacteria (Bacillus subtilis and Staphylococcus aureus as Gram-positive, and Escherichia coli as Gram-negative) were employed to test the proposed system. HS-Van functionalized GNAs (GNA@Van) captured Gram-positive bacteria with high specificity. Also, the bacteria captured by GNA@Van (GNA@Van@Bct) systems showed high signal-to-noise SERS signals with high reproducibility. Addition of AuNP@Van to GNA@Van@Bct resulted in the emergence of a sandwich system (GNA@Van@Bct@Van@AuNP). This system led to a further enhanced SERS signal. The chemometric analysis of GNA@Van@Bct@Van@AuNP enabled the obvious discrimination and detection of Gram-positive bacteria. For comparison, we also tested a smooth gold surface with the same procedure and a similar trend was observed with lower SERS activity.

Poly(L-DOPA)-mediated bimetallic core-shell nanostructures of gold and silver and their employment in SERS, catalytic activity, and cell viability.

Core-shell gold nanorod (AuNR)@silver (Ag) nanostructures with their unique properties have gained enormous interest and are widely utilized in various applications including sensor systems, catalytic reactions, diagnosis, and therapy. Despite the recent progress, simple, effective, low-cost, and easy-to-tune strategies are heavily required to fabricate these nanoparticles (NP) systems. For this, we propose the employment of the polymer of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) as a ligand molecule. A conformal thin layer of polymer of L-DOPA (PLDOPA) with its various functional groups enabled the reduction of silver ions onto the AuNRs and stabilization of the resultant NPs without using any surfactant, reducing agent, and seed material. The shape and growth model of the AuNR@Ag nanostructures was manipulated by simply tuning the amount of silver ions. This procedure created different NP morphologies ranging from concentric to acentric/island shape core-shell nanostructures. Also, even at the highest Ag deposition, the PLDOPA layer is still conformally present onto the Au@Ag core-shell NRs. The unique properties of NP systems provided remarkable characteristics in surface-enhanced Raman spectroscopy, catalytic activity, and cell viability tests.

The cytotoxic and apoptotic effects of beta-blockers with different selectivity on cancerous and healthy lung cell lines.

ß-blockers having specific affinities to ß-adrenergic receptors are routinely used to treat cardiovascular problems. Additionally, it has been demonstrated that these drugs can be effective in treating apoptosis-related diseases. The current study was conducted to investigate the cytotoxic and apoptotic effects of ß-1 selective esmolol, ß-2 selective ICI-118,551, and non-selective nadolol blockers on the cancerous and healthy lung cells. MTT test was used to evaluate cytotoxicity. Apoptotic actions were examined by using Annexin V-FITC/PI assay, JC-1 staining, ROS test, and the determination of the caspase-4 and -9, Bcl-2, Bax, Bax/Bcl-2, and JNK levels. Although the MRC-5 showed greater resistance than A549 cells, the ß-blockers at 150-250 µM exhibited different levels of cytotoxic effect on both lung cell lines. Esmolol was found to be the most ineffective blocker and the increases in Bcl-2 protein levels were appeared to be effective in resistance to this drug. The increases in reactive oxygen species (ROS) together with the increase in caspase-4 and Bax protein levels have been shown to play a role in ICI-118,551 induced lung cell death. Nadolol was the most effective blocker increasing the total apoptotic cell population in both lung cells, which was based on both mitochondrial and endoplasmic reticulum stress. When the selectivities of the ß-blockers are considered, it seems that ß-2 specific antagonism predominantly mediated the death of lung cells, and the overwhelming factors causing apoptosis mainly varied depending on the selectivity of the blockers.

Design, synthesis and biological evaluation of novel bischalcone derivatives as potential anticancer agents.

Building on our previous work that discovered chalcone as a promising pharmacophore for anticancer activity, we have various other chalcone derivatives and have synthesized a series of novel bischalcone to explore their anticancer activity. Among all tested compounds, compounds 6a, 6b, and 6c showed the highest antiproliferative activity against A-549 cancer cell lines with the average IC50 values of 4.18, 4.52, and 5.05 µM, respectively. Moreover, compound 6c showed high antiproliferative activity against the Caco-2 cell line; thus, it was 2- and 4-fold more active than the reference compounds, i.e., methotrexate and capecitabine. Compound 6a also induced cell-cycle arrest in the S phase, whereas compounds 6b and 6c were observed to stop at the G0/G1 phase. Thereafter, we evaluated that compound 6c also had the highest apoptosis/necrosis ratio than other compounds and the standard compound. The anticancer property of the 6c was also supported by molecular docking studies carried out on the EGFR and HER2 receptors. Overall, we expect that these compounds can be further developed for the potential treatment of lung cancer.

Gastroprotective effects of oleuropein and thymol on indomethacin-induced gastric ulcer in Sprague-Dawley rats.

Ethnopharmacological studies demonstrated that thymol (Thym) and oleuropein (Ole) have therapeutic potential for gastric ulcers. The molecular mechanism underlying the gastroprotective effects of these compounds have not been elucidated yet especially for their individual and combination use at high dose. Therefore, this study was conducted to explore their gastroprotective mechanisms on indomethacin (Indo)-induced gastric ulcer model. Ole (50,100, 250, and 500 mg/kg) and Thym (50,100, 200, and 500 mg/kg) were orally administered to the rats 10 min before the induction of ulcer with Indo. The combination of 500 mg/kg doses of Ole and Thym were applied. The gastric mucosa was evaluated histopathologically. Moreover, TAC/TOS, tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), endothelial nitric oxide synthase (eNOS), and caspase-3 levels were assessed by ELISA and the caspase-3 and TNF-α expressions were quantified by qRT-PCR. Indo-induced histopathological changes while Ole and Thym pretreatment prevented these effects. Unlike the 500 mg/kg dose of Ole treatment, the 500 mg/kg dose of Thym administration enhanced these damages. The decreased TAC, PGE2 levels and increased TOS, eNOS, TNF-α, caspase-3 levels were obtained in Indo group. However, these changes were reversed by Ole and Thym groups except the 500 mg/kg dose of Thym and the combination treatment groups. Similar trends were observed in the caspase-3 and TNF-α expression levels. These results demonstrated that enhanced inflammation, oxidant/antioxidant imbalance, and apoptotic activities were occurred in Indo, 500 mg/kg dose of Thym and the combination treatment groups while not in the other groups. The findings demonstrated the gastroprotective ability of Ole and low doses of Thym in gastric ulcer models.

The efficacy of oleuropein against non-steroidal anti-inflammatory drug induced toxicity in rat kidney.

Indomethacin is generally used in clinical therapeutics as a non-steroidal anti-inflammatory drug. However, its use has been limited due to the gastrointestinal and renal toxic effects of this drug. These toxic effects were associated with not only the inhibition of prostaglandin synthesis but also drug-elevated oxidative stress. To ameliorate these toxicities, natural antioxidants can be used as an alternative and/or combination therapies. Therefore, the current study was conducted to assess the renoprotective effects of oleuropein against indomethacin-induced renal damages. Male Sprague-Dawley rats were pretreated with oleuropein (75, 150, and 300 mg/kg), and then treated with indomethacin (25 mg/kg). To evaluate kidney function, serum blood urea nitrogen, uric acid, and creatinine were measured. In addition, prostaglandin E2 , tumor necrosis factor-alpha, endothelial nitric oxide synthase, caspase-3, oxidant/antioxidant status, and 8-Oxo-2'-deoxyguanosine levels were determined for the antioxidative and anti-inflammatory effects of oleuropein. Tissue sections were also histopathologically assessed. The biochemical and histopathological analysis proved the toxic effects of indomethacin on kidney. However, the pretreatment with oleuropein (300 mg/kg) protects kidney from indomethacin-induced damages. Our study proved that prior administration of oleuropein has renoprotective activity against indomethacin-associated toxicities.

Hepatoprotective Role of Thymol in Drug-Induced Gastric Ulcer Model.

INTRODUCTION AND AIM: Indo is widely one of the non-steroidal anti-inflammatory drugs and one of the common toxic effects of this drug is hepatic failure. Thymol is a monoterpene phenol with many different pharmacological activities. However, up to now its hepatoprotective effects on Indo-induced gastric ulcer model in rats have not been explored yet. MATERIAL AND METHODS: Thirty five Sprague-Dawley rats were divided into seven groups: control, ulcer control (30 mg/kg Indo), Indo + reference standard (50 mg/kg Rantidine), Indo + Thymol (75, 100, 250 and 500 mg/kg) groups. 10 minutes after the induction of ulcer with Indo; Thymol was orally administered to the rats. Liver function enzymes (AST, ALT and LDH) were measured from serum samples. TOS/TAC, TNF-α and PGE2 levels, eNOS and Caspase-3 activity were assessed from tissue homogenate samples. In addition, histopathologic analysis on liver sections was performed. RESULTS: Indo significantly increased the levels of hepatic enzymes, TNF-α and eNOS, and caspase-3 activation, while decreased PGE2 levels. Furthermore, it induced oxidative stress as evidenced by elevated TOS and decreased TAC levels. However, Thymol treatment induced a significant improvement in these parameters, especially in 250 mg/kg dose. On the other hand, treatment with Thymol 500 mg/kg dramatically affected the parameters much worse than the Indo treated group. CONCLUSION: The findings of the current study demonstrated that Thymol administration significantly ameliorated liver injury due to Indo toxicity. This effect of Thymol (250 mg/kg) may be mediated by its anti-oxidative or anti-inflammatory effect, and up-regulation the synthesis of PGE2.

Preparation and Characterization of Nanosuspensions of Triiodoaniline Derivative New Contrast Agent, and Investigation into Its Cytotoxicity and Contrast Properties.

Iodine-based contrast agents have limitations such as rapid clearance, potential renal toxicity, non-specific blood pool distribution, headache, and adverse events. Nowadays, it is quite common to work with nanosized systems in order to eliminate the side effects of contrast agents. This study aims to synthesize a new iodinated contrast agent, prepare its nanosuspension by using the nanoprecipitation method, investigate its cytotoxicity, and compare its contrast properties with iohexol and iopromide through in-vitro experiments. The values of nanosuspension particle size and zeta potential have been found to be ~ 400 nm and ~ (-) 15 mV, respectively. In-vitro cellular viability findings indicated that the nanosuspension has lower cytotoxicity than the iohexol and iopromide. In the computed tomography (CT) imaging study of contrast features of nanosuspensions and two commercial agents, which involved 86 CT examinations using 31 parameters and two different devices, it was found that iodine had a stronger presence in its nanosuspension form than in iohexol and iopromide, which were the other two commercial contrast agents, when used in equal amounts. Thus in the case of nanosuspensions contrast brightness was achieved by using less iodine, while the same brightness could be obtained with higher doses of iohexol and iopromide. CT imaging therefore be done without much chemical use, which indicates that it may witness fewer side effects in the future.

Monitoring chemically and green-synthesized silver nanoparticles in maize seedlings via surface-enhanced Raman spectroscopy (SERS) and their phytotoxicity evaluation.

The emergence of nanomaterials in consumer products has increased concern for their potential hazards in the environment and biological systems. Therefore, the monitoring of nanoparticles in biological systems is of great importance. Despite the numerous attempts, the methods to evaluate the uptake, translocation, and accumulation of nanomaterials inside the plant tissue are still limited. In this study, for the first time, we proposed the monitoring of the silver nanoparticles (AgNPs) in different tissues of the plant through surface-enhanced Raman spectroscopy (SERS) approach. For this, chemically (Che-AgNPs) and green-synthesized AgNPs (Gr-AgNPs) were prepared properly and their surfaces were functionalized with Raman-active molecule. With the contribution of electromagnetic enhancement, our NP systems provided high signal-to-noise SERS spectra. After exposure to NPs to maize seedlings as a model plant, we detected that AgNPs were accumulated mainly in the epidermis and cortex of the root and phloem parts of the shoot. Highly distinctive SERS spectra were collected from the root and shoot cross-section of each NP system. Also, the accumulation of the AgNPs was furtherly confirmed through inductively-coupled mass spectrometry and scanning electron microscopy analysis. Moreover, the exposure of AgNPs to maize seedlings led to remarkable alterations in both phytotoxic and biomolecular indicators including chlorophyll, protein and, antioxidant enzymes.

Niobium-oxynitride coatings for biomedical applications: Its antibacterial effects and in-vitro cytotoxicity.

316L Stainless Steel (SS) has been widely used in many medical applications, such as orthopedic prostheses and cardiovascular implants due to its good mechanical properties and resistance to corrosion. Despite its superior features, SS has bio-functionality problems. In this study, niobium oxynitride coatings were deposited onto 316L SS substrates to improve their biocompatibility using a reactive radio frequency (RF) magnetron sputtering technique. The nitrogen flow was fixed, and the nitrogen to oxygen flow ratio was set to 2, 5 and 10 to investigate the effect of oxygen concentration on biocompatibility and the antibacterial behavior of the oxynitride films. The microstructure, morphology and wettability properties of the coatings were analyzed by scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and an optical tensiometer. The antibacterial activities of coated and uncoated 316L substrates were tested against S. aureus and E. coli bacterial strains. The cytotoxic effects of NbOxNy-coated and uncoated substrates were evaluated on human fibroblast cells. The results showed that niobium oxynitride coatings were not cytotoxic and exhibited more antibacterial activity in comparison to the uncoated ones.

Gold nanorod arrays enable highly sensitive bacterial detection via surface-enhanced infrared absorption (SEIRA) spectroscopy.

Infrared (IR) spectroscopy is a unique and powerful method in the identification, characterization, and classification of chemical and biological molecules. However, the low absorbance of biological molecules has arisen as a major bottleneck and inhibits the application of IR in practical applications. To overcome this limitation, in the last four decades, surface-enhanced IR absorption (SEIRA) spectroscopy has been proposed and has become the focus of interest in various applications. In this study, for the first time, we proposed the employment of 3D anisotropic gold nanorod arrays (GNAs) as a highly active SEIRA platform in bacterial detection. For this, GNA platforms were fabricated through an oblique angle deposition (OAD) approach by using a physical vapor deposition (PVD) system. OAD of gold at proper deposition angle (10°) created closely-packed and columnar gold nanorod structures onto the glass slides in a well-controlled manner. GNA platform was tested as a SEIRA system in three different species of bacteria (Escherichia coli, Staphylococcus aureus, and Bacillus subtilis) by collecting IR spectra of each bacteria from different parts of GNA. The employment of GNA provided robust IR spectra with high reproducibility and signal-to-noise ratio. For the comparison, IR spectra of each bacteria were collected from aluminum foil and a smooth gold surface (SGS). No or very low IR spectra were observed in comparison to the GNA platform for these substrates. Unsupervised (PCA, HCA) and supervised (SIMCA, LDA, and SVM classification) machine learning analysis of bacteria spectra obtained from GNA substrate indicated that all bacteria samples can be detected and identified without using a label-containing biosensor, in a fast and simple manner.

Inula graveolens induces selective cytotoxicity in glioblastoma and chronic leukemia cells.

OBJECTIVE: Crude oil extracts, components of extracts, and ethanolic extracts of Inula graveolens possess various pharmacological activities on various cancer cells including antioxidative and antiproliferative effects. Aqueous extract of this species has not been investigated on the liquid malignancies and solid tumors with a high incidence of treatment refractoriness and poor survival outcomes such as glioblastoma and leukemia. Hence, the present study aimed to evaluate the cytotoxic efficiency of I. graveolens aqueous extracts on human glioblastoma multiforme and chronic myelogenous leukemia cell lines in comparison to non-cancerous primary rat cerebral cortex and human peripheral blood mononuclear cells. METHODS: The cells were treated with the extracts of I. graveolens (125-1000 µg/mL) for 48 h, the cellular viability was identified using 3'-(4,5dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and lactate dehydrogenase release was measured to determine the cytotoxic potential. Total oxidant status and apurinic/apyrimidinic endodeoxyribonuclease 1 assays were used to determine the oxidative status of cells and DNA damage, respectively. RESULTS: I. graveolens showed selective cytotoxicity toward human glioblastoma multiforme and chronic myelogenous leukemia cell lines and exhibited a higher antiproliferative effect against cancer cells in comparison to non-cancerous cells. Moreover, it significantly reduced the apurinic/apyrimidinic endodeoxyribonuclease 1 levels on both cancer cell lines as compared with their control cells without changing the levels of an oxidative stress marker. CONCLUSION: The extracts of I. graveolens have anti-cancer potential on human glioblastoma multiforme and chronic myelogenous leukemia cell lines without causing oxidative stress.

The targets of ß-sitosterol as a novel therapeutic against cardio-renal complications in acute renal ischemia/reperfusion damage.

This research is the first to use ß-sitosterol on myocardial and renal tissues in renal ischemia/reperfusion (IR) damage. Female Wistar rats were randomly divided into three groups: control (sham), renal IR (50 min ischemia - 3 h reperfusion), and renal IR + 150 mg/kg/p.o. ß-sitosterol (the rats were treated with ß-sitosterol orally once 1 h before the IR procedure). ß-Sitosterol pretreatment caused an increase in superoxide dismutase and glutathione activities and a decrease in malondialdehyde levels in the kidney and heart. Moreover, it alleviated histopathological changes and downregulated the levels of tumor necrosis factor-alpha and interleukin-6 and upregulated the levels of endothelial nitric oxide synthase. As conclusion, the potential of ß-sitosterol for renal and cardiac necrosis and apoptosis appears to act by limiting inflammatory response and oxidative stress. Thus, the potential of this compound is noteworthy and may serve as a potential therapeutic in the treatment of acute organ damages due to renal IR.

Propolis and Its Combination with Boric Acid Protect Against Ischemia/Reperfusion-Induced Acute Kidney Injury by Inhibiting Oxidative Stress, Inflammation, DNA Damage, and Apoptosis in Rats.

Ischemia reperfusion (I/R) injury which causes kidney dysfunction is one of the most studied diseases directly linked to oxidative stress. In this regard, it is important to protect cells against damage by inducing antioxidant response. Herein, we aimed to evaluate the therapeutic roles and possible mechanisms of propolis and boric acid in kidney I/R injury based on relevant basic research and clinical studies. Sprague-Dawley rats were subjected to 50 min of ischemia followed by 3 h of reperfusion. Animals were randomly divided into a control group (the abdominal wall was just opened and closed), an I/R injury group, the propolis intervention group (200 mg/kg, intragastric administration, 1 h before ischemia), boric acid intervention group (14 mg/kg, intragastric administration 1 h before ischemia), and the propolis + boric acid intervention group (intragastric administration 1 h before ischemia). Kidney function, the antioxidant defensive system, and renal damage were assessed. In addition, the oxidative stress and inflammatory status were estimated in renal tissue. Furthermore, DNA damageand apoptosis were detected by immunohistochemistry. When compared with I/R group, propolis alone and especially propolis + boric acid groups significantly improved functional parameters. While the antioxidant response was increased, renal injury size and apoptosis were significantly decreased in both groups. Also, the MDA and TNF-α levels besides the 8-OHdG formation were downregulated. According to these outcomes, it can be said that especially propolis together with boric acid ameliorates kidney injury caused by I/R through acting as an antioxidant, anti-inflammatory, and antiapoptotic agent. In conclusion, propolis alone and its combination with boric acid could be developed as therapeutic agents against serious renal I/R injuries.