Evaluation of the cytotoxic activities of the essential oil from Pistacia atlantica Desf. oleoresin on human gastric cancer cell lines.

Numerous herbal products have been the subject of research regarding their potential role in cancer prevention or adjuvant therapy. Pistacia atlantica and its main phytochemicals have garnered significant attention for their potential anti-cancer effects. The study aimed to assess the growth inhibitory effects of P. atlantica essential oil (PAEO) on MKN-45 and AGS cells. This study quantified the volatile compounds in PAEO using Gas Chromatography-Mass Spectrometry (GC-MS). Subsequently, MKN-45 and AGS cells were treated with varying concentrations of PAEO (5%, 2.5%, 1.25%, 0.625%, 0.3125%, 0.156%, 0.0781%, 0.0391%, 0.0195%) for 24 h. Cell viability was evaluated through the MTT assay. The impact of PAEO on gene expression was investigated by quantifying the mRNA levels of Bax and Bcl2 in the various experimental groups using quantitative Real-Time PCR (qRT-PCR) analysis. Additionally, flow cytometry was utilized to evaluate apoptosis in the treated cells. The analysis of PAEO revealed that α-pinene was the predominant monoterpene, constituting 87.9% of the oil composition. The cytotoxic effects of PAEO were evaluated, and it was found that the oil significantly reduced the viability of MKN-45 and AGS cells. The IC50 for MKN-45 cells was determined to be 1.94 × 10-3% after 24 h of treatment, while for AGS cells the IC50 was 2.8 × 10-3% after 24 h. Additionally, the research revealed that PAEO triggered a notable rise in apoptotic cells in both AGS and MKN-45 cell lines. Moreover, at the molecular level, the findings indicated an increase in Bax expression and a decrease in Bcl2 mRNA expression, providing further evidence of the induction of apoptosis in both MKN-45 and AGS cell lines following PAEO treatment. The findings of this study offer evidence supporting the cytotoxic effects of PAEO on gastric cancer cell lines by promoting apoptosis. The findings suggest that PAEO may offer potential as a therapeutic candidate in managing and treating gastric cancer.

The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance.

Globally, hepatic cancer ranks fourth in terms of cancer-related mortality and is the sixth most frequent kind of cancer. Around 80% of liver cancers are hepatocellular carcinomas (HCC), which are the leading cause of cancer death. It is well known that HCC may develop resistance to the available chemotherapy treatments very fast. One of the biggest obstacles in providing cancer patients with appropriate care is drug resistance. According to reports, more than 90% of cancer-specific fatalities are caused by treatment resistance. By binding to the 3'-untranslated region of target messenger RNAs (mRNAs), microRNAs (miRNAs), a group of noncoding RNAs which are around 17 to 25 nucleotides long, regulate target gene expression. Moreover, they play role in the control of signaling pathways, cell proliferation, and cell death. As a result, miRNAs play an important role in the microenvironment of HCC by changing immune phenotypes, hypoxic conditions, and acidification, as well as angiogenesis and extracellular matrix components. Moreover, changes in miRNA levels in HCC can effectively resist cancer cells to chemotherapy by affecting various cellular processes such as autophagy, apoptosis, and membrane transporter activity. In the current work, we narratively reviewed the role of miRNAs in HCC, with a special focus on tumor microenvironment and drug resistance.

Protective effect of thymoquinone nanoemulsion in reducing the cardiotoxic effect of 5-fluorouracil in rats.

5-Fluorouracil (5-FU), which is one of the most widely used chemotherapy drugs, has various side effects on the heart. Thymoquinone (TMQ), the main bioactive component of Nigella sativa, has antioxidant and protective effects against toxicity. In this study, we investigated the protective effect of thymoquinone against cardiotoxicity caused by 5-FU in vitro and in vivo models. H9C2 cells were exposed to 5-FU and TMQ, and cell viability was evaluated in their presence. Also, 25 male Wistar rats were divided into five control groups, 5-FU, 2.5, and 5 mg TMQ in nanoemulsion form (NTMQ) + 5-FU and 5 mg NTMQ. Cardiotoxicity was assessed through electrocardiography, cardiac enzymes, oxidative stress markers, and histopathology. 5-FU induced cytotoxicity in H9c2 cells, which improved dose-dependently with NTMQ cotreatment. 5-FU caused body weight loss, ECG changes (increased ST segment, prolonged QRS, and QTc), increased cardiac enzymes (aspartate aminotransferase [AST], creatine kinase-myocardial band [CK-MB], and lactate dehydrogenase [LDH]), oxidative stress (increased malondialdehyde, myeloperoxidase, nitric acid; decreased glutathione peroxidase enzyme activity), and histological damage such as necrosis, hyperemia, and tissue hyalinization in rats. NTMQ ameliorated these 5-FU-induced effects. Higher NTMQ dose showed greater protective effects. Thus, the results of our study indicate that NTMQ protects against 5-FU cardiotoxicity likely through antioxidant mechanisms. TMQ warrants further research as an adjuvant to alleviate 5-FU chemotherapy side effects.

Kaempferol alleviates bisphenol A reproductive toxicity in rats in a dose-dependent manner.

BACKGROUND: Endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), are a major cause of male infertility by disrupting spermatogenesis. OBJECTIVE: Here, we examined the potential protective benefits of kaempferol (KMF), a flavonol known for its antioxidant properties, on BPA-induced reproductive toxicity in adult male rats. METHODS: Human skin fibroblast cells (HNFF-P18) underwent cell viability assays. Thirty-five male Wistar rats were assigned to four groups: 1) control, 2) BPA (10 mg/kg), 3,4) BPA, and different dosages of KMF (1 and 10 mg/kg). The study examined the rats' testosterone serum level, antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD), oxidative markers malondialdehyde (MDA) and total antioxidant capacity (TAC), body weight, weight ratios of testis and prostate, and histopathological examinations. RESULTS: The study revealed that using KMF to treat rats exposed to BPA increased cell viability. Moreover, the rats' testosterone levels, which BPA reduced, showed a significant increase after KMF was included in the treatment regimen. Treatment with BPA led to oxidative stress and tissue damage, but simultaneous treatment with KMF restored the damaged tissue to its normal state. Histopathology studies on testis and prostate tissues showed that KMF had an ameliorative impact on BPA-induced tissue damage. CONCLUSIONS: The research suggests that KMF, a flavonol, could protect male rats from the harmful effects of BPA on reproductive health, highlighting its potential healing properties.

The effect of melatonin on capecitabine-induced hepatic and renal toxicity in rats.

BACKGROUND: Capecitabine (CAPE), an antimetabolite chemotherapy, can induce hepatic and renal toxicity. Melatonin (MEL), a neurohormone, possesses antioxidant, anti-apoptotic and anti-inflammatory effects. This study investigated the impact of MEL on capecitabine-induced hepatic and renal toxicity. METHODS AND MATERIALS: Twenty-five male Wistar rats were categorized into five groups for the study. The groups included a control group, MEL10 group (rats receiving daily intraperitoneal injections of 5 mg/kg MEL), CAPE 500 group (rats receiving weekly intraperitoneal injections of 500 mg/kg CAPE), CAPE + MEL five group, and CAPE + MEL 10 group. All groups were treated for a duration of 6 weeks. Various hematological, serological, biochemical, and histopathological assessments were conducted to evaluate the objective of the study. RESULTS: The administration of CAPE led to significant liver and kidney toxicity, as evidenced by elevated levels of malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), as well as serological markers including AST, ALT, ALP, BUN, and creatinine. CAPE exposure also resulted in a reduction in total antioxidant capacity (TAC) and glutathione peroxidase (GPx) levels. Histological examination revealed hyperemia in both liver and kidney tissues exposed to CAPE. However, treatment with MEL demonstrated positive effects. MEL administration alleviated oxidative stress, reduced levels of liver enzymes, BUN, and creatinine, and ameliorated histopathological degenerations. MEL also increased GPx and TAC levels. Moreover, MEL treatment aided in restoring the body weight that was lost due to CAPE exposure. CONCLUSION: Our findings indicated that the administration of MEL in rats significantly enhanced the hepatic and renal toxicity induced by CAPE.

Therapeutic benefit of melatonin in 5-fluorouracil-induced renal and hepatic injury.

Nephrotoxicity and hepatotoxicity include increased oxidative stress and apoptosis; as a result, liver and kidney damage are related to its pathogenesis. These are significant side effects caused in cancer patients treated with 5-FU. In the research, 25 rats were divided into five groups, including control, 5-FU and 5-FU + 2.5, 5 and 10 mg/kg melatonin (MEL), and the protective impact of MEL against 5-FU-induced hepatorenal damage in rats was investigated. 5-FU caused significant harm, resulting in severe renal failure and histopathological changes. It also increased BUN, creatinine and hepatic function markers levels while decreasing superoxide dismutase and glutathione peroxidase activity. Additionally, 5-FU led to a notable increase in malondialdehyde content. However, MEL co-administration to rats reversed most biochemical and histologic effects. In the control and MEL + 5-FU groups, the values were comparable. The doses of MEL treatment had a significant positive impact on 5-FU-induced oxidative stress, apoptosis, lipid peroxidation and kidney damage. Our data concluded that MEL has an ameliorative effect on hepatorenal damage caused by 5-FU.

Investigating and assessing the risk of remaining toxins in cucumbers grown in fields and greenhouses in Mazandaran Province.

To address concerns regarding the potential health risks associated with residual chemicals in food products, this study aimed to assess the concentrations of residual Benomyl, Malathion, and Diazinon in cucumbers and evaluate the associated health risks for consumers. This descriptive study involved the collection of 100 cucumber samples from both field and greenhouse cultivation in Mazandaran Province. These samples were subsequently sent to the laboratory for analysis. Following sample preparation and digestion, we determined the levels of residual Malathion, Benomyl, and Diazinon using HPLC. The results showed an average residual Malathion concentration of 2.1 ± 0.04 mg/kg in field-grown cucumbers and 2.04 ± 1.5 mg/kg in greenhouse-cultivated cucumbers. Meanwhile, the average residual Diazinon concentration was 5.1 ± 0.2 mg/kg in field samples and 4.99 ± 3.23 mg/kg in greenhouse samples. The average concentrations of residual Benomyl were found to be 0.94 ± 0.65 mg/kg in field-grown cucumbers and 0.39 ± 0.2 mg/kg in greenhouse-cultivated cucumbers. Furthermore, a health risk assessment model was employed to evaluate the cumulative risk of these residual pesticides in cucumbers. The analysis revealed that residual Benomyl levels ranged from 0 to 24.33 mg/kg, while Malathion ranged from 0 to 9.25 mg/kg, and Diazinon ranged from 0 to 6.8 mg/kg. Notably, in some areas, the average concentration of all three pesticides exceeded the guidelines set by the WHO and the European Union. Additionally, the cumulative risk assessment (represented by MOET value of 2655) indicated that the combined presence of residual Malathion, Benomyl, and Diazinon in field-cultivated cucumbers posed a health risk. Based on current per capita consumption rates, the study's health risk index results raised concerns about the safety of consuming these residual byproducts. Given the growing use of chemicals in agricultural and horticultural practices, it is imperative to monitor residual pesticides to assess dietary intake and ensure consumer safety in food production.

5-Flourouracil-induced toxicity in both male and female reproductive systems: A narrative review.

The chemotherapeutic drug 5-flourouracil (5FU) is frequently used to treat a wide range of solid malignant tumors, such as colorectal, pancreatic, gastric, breast, and head and neck cancers. Its antitumoral effects are achieved by interfering with the synthesis of RNA and DNA and by inhibiting thymidylate synthase in both malignant and non-malignant cells. Therefore, it can be responsible for severe toxicities in crucial body organs, including heart, liver, kidney, and reproductive system. Given the fact that 5FU-induced reproductive toxicity may limit the clinical application of this drug, in this study, we aimed to discuss the main locations and mechanisms of the 5FU-induced reproductive toxicity. Initially, we discussed the impact of 5FU on the male reproductive system, which leads to damage of the seminiferous epithelial cells and the development of vacuoles in Sertoli cells. Although no noticeable changes occur at the histopathological level, there is a decrease in the weight of the prostate. Additionally, 5FU causes significant abnormalities in spermatogenesis, including germ cell shedding, spermatid halo formation, polynucleated giant cells, and decreased sperm count. Finally, in females, 5FU-induced reproductive toxicity is characterized by the presence of atretic secondary and antral follicles with reduced numbers of growing follicles, ovarian weight, and maturity impairment.

Toxic mechanisms of cadmium and exposure as a risk factor for oral and gastrointestinal carcinomas.

Incidence and mortality rates of gastrointestinal (GI) and oral cancers are among the highest in the world, compared to other cancers. GI cancers include esophageal, gastric, colon, rectal, liver, and pancreatic cancers, with colorectal cancer being the most common. Oral cancer, which is included in the head and neck cancers category, is one of the most important causes of death in India. Cadmium (Cd) is a toxic element affecting humans and the environment, which has both natural and anthropogenic sources. Generally, water, soil, air, and food supplies are reported as some sources of Cd. It accumulates in organs, particularly in the kidneys and liver. Exposure to cadmium is associated with different types of health risks such as kidney dysfunction, cardiovascular disease, reproductive dysfunction, diabetes, cerebral infarction, and neurotoxic effects (Parkinson's disease (PD) and Alzheimer's disease (AD)). Exposure to Cd is also associated with various cancers, including lung, kidney, liver, stomach, hematopoietic system, gynecologic and breast cancer. In the present study, we have provided and summarized the association of Cd exposure with oral and GI cancers.

The Role of microRNAs in Regulating Cancer Cell Response to Oxaliplatin-Containing Regimens.

Oxaliplatin (cyclohexane-1,2-diamine; oxalate; platinum [2+]) is a third-generation chemotherapeutic drug with anticancer effects. Oxaliplatin has a role in the treatment of several cancers. It is one of the few drugs which can eliminate the neoplastic cells of colorectal cancer. Also, it has an influential role in breast cancer, lung cancer, bladder cancer, prostate cancer, and gastric cancer. Although oxaliplatin has many beneficial effects in cancer treatment, resistance to this drug is in the way to cure neoplastic cells and reduce treatment efficacy. microRNAs are a subtype of small noncoding RNAs with ∼22 nucleotides that exist among species. They have diverse roles in physiological processes, including cellular proliferation and cell death. Moreover, miRNAs have essential roles in resistance to cancer treatment and can strengthen sensitivity to chemotherapeutic drugs and regimens. In colorectal cancer, the co-treatment of oxaliplatin with anti-miR-19a can partially reverse the oxaliplatin resistance through the upregulation of phosphatase and tensin homolog (PTEN). Moreover, by preventing the spread of gastric cancer cells and downregulating glypican-3 (GPC3), MiR-4510 may modify immunosuppressive signals in the tumor microenvironment. Treatment with oxaliplatin may develop into a specialized therapeutic drug for patients with miR-4510 inhibition and glypican-3-expressing gastric cancer. Eventually, miR-122 upregulation or Wnt/ß-catenin signaling suppression boosted the death of HCC cells and made them more sensitive to oxaliplatin. Herein, we have reviewed the role of microRNAs in regulating cancer cells' response to oxaliplatin, with particular attention to gastrointestinal cancers. We also discussed the role of these noncoding RNAs in the pathophysiology of oxaliplatin-induced neuropathic pain.

miRNAs and Multiple Myeloma: Focus on the Pathogenesis, Prognosis, and Drug Resistance.

Multiple myeloma (MM) produces clonal plasma cells and aberrant monoclonal antibody accumulation in patients' bone marrow (BM). Around 1% of all cancers and 13% of hematological malignancies are caused by MM, making it one of the most common types of cancer. Diagnostic and therapeutic methods for managing MM are currently undergoing extensive research. MicroRNAs (miRNAs) are short noncoding RNAs that reduce or inhibit the translation of their target mRNA after transcription. Because miRNAs play an influential role in how myeloma develops, resources, and becomes resistant to drugs, miRNA signatures may be used to diagnose, do prognosis, and treat the myeloma response. Consequently, researchers have investigated the levels of miRNA in plasma cells from MM patients and developed tools to test whether they directly impacted tumor growth. This review discusses the latest discoveries in miRNA science and their role in the development of MM. We also emphasize the potential applications of miRNAs to diagnose, prognosticate, and treat MM in the future.

Iron; Benefits or threatens (with emphasis on mechanism and treatment of its poisoning).

Iron is a necessary biological element and one of the richest in the human body, but it can cause changes in cell function and activity control. Iron is involved in a wide range of oxidation - reduction activities. Whenever iron exceeds the cellular metabolic needs, its excess causes changes in the products of cellular respiration, such as superoxide, hydrogen peroxide and hydroxyl. The formation of these compounds causes cellular toxicity. Lack of control over reactive oxygen species causes damages to DNA, proteins, and lipids. Conversely, superoxide, hydrogen peroxide and hydroxyl are reactive oxygen species, using antioxidants, restoring DNA function, and controlling iron stores lead to natural conditions. Iron poisoning causes clinical manifestations in the gastrointestinal tract, liver, heart, kidneys, and hematopoietic system. When serum iron is elevated, serum iron concentrations, total iron-binding capacity (TIBC) and ferritin will also increase. Supportive care is provided by whole bowel irrigation (WBI), esophagogastroduodenoscopy is required to evaluate mucosal injury and remove undissolved iron tablets. The use of chelator agents such as deferoxamine mesylate, deferasirox, deferiprone, deferitrin are very effective in removing excess iron. Of course, the combined treatment of these chelators plays an important role in increasing iron excretion, and reducing side effects.

The protective effects of silymarin nanoemulsion on 5-fluorouracil-induced gastrointestinal toxicity in rats.

5-Fluorouracil (5FUra) is the third most popular chemotherapeutic component employed to treat solid tumors. In the present study, we aimed to appraise the silymarin (SM) and silymarin nanoemulsion (SMN) effect on 5FUra-induced gastrointestinal toxicity in adult male rats. A total of 30 male Wistar rats were divided into 6 groups including the control (Crl) group, and groups treated with SMN (5 mg.kg-1), SM (5 mg.kg-1), 5FUra + SMN (5 mg.kg-1), and 5FUra + SM (5 mg.kg-1) by IP injection for 14 days. And gastrointestinal toxicity was induced by a single intraperitoneal (IP) injection of 5FUra (100 mg.kg-1) for the last group in the study. Treating rats with SM and SMN diminished elevating malondialdehyde (MDA) levels, and improved total antioxidant capacity (TAC) levels. Also, the intensity of mRNA expression of interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) caused by 5FUra in the gastrointestinal tissue tract, and macroscopic oral ulcerations decreased, ass well as weight loss was prevented, particularly in the SMN group. Moreover, in the microscopic scope, there were significant improvements in the levels of hyperemia, hyaline, and inflammatory cell infiltration in the tongue, esophagus, and intestinal tissues in the FUra + SMN and FUra + SM groups compared to 5FUra. Hence, treatment with SM and SMN reduced oxidative stress, histopathological degeneration, and gene expression of inflammatory markers in the gastrointestinal tract. According to the results, treatment with SM and SMN markedly decreases the gastrointestinal toxicity caused by 5FUra.

Thymoquinone protects against 5-Fluorouracil-induced mucositis by NF-κß and HIF-1 mechanisms in mice.

Mucositis is among the most common side effects of 5-Fluorouracil (5-FU) and other cancer therapeutic drugs. Thymoquinone (TQ), a bioactive constituent extracted from Nigella sativa, has antioxidant and anti-inflammatory properties and can modify acute gastrointestinal injury. To investigate the effects of TQ on mucositis induced by 5-FU, studied animals were divided into four groups: control, 5-FU unit dose (300 mg/kg) to cause oral and intestinal mucositis (OM and IM), TQ (2.5 mg/kg) and TQ (2.5 mg/kg) plus 5-FU. Due to The molecular mechanisms, it was confirmed that the expression of NF-κß and HIF-1 increases in OM. The serum levels of malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD), as well as pathological parameters, were assessed. Based on our results, the nuclear factor-kappa ß gene expression in the tongue was downregulated significantly in the 5-FU + TQ compared to the 5-FU. TQ treatment can diminish MDA, and a reduction in oxidative stress was shown. TQ could also reduce the severity of tissue destruction and damaging effects induced by 5-FU on the tongue and intestine. We also observed lower villus length and width in the intestine of the 5-FU group compared to the control group. According to our research's pathological, biochemical, and molecular results, treatment with TQ as an anti-inflammatory and antioxidant compound may be the potential to improve and treat 5-FU-induced OM and IM, and TQ could be used against cancer treatment drugs and exhibit fewer adverse effects.

Determining the Antibacterial Effect of Mentha Longifolia Essential Oil on Cariogenic Bacteria and Its Compounds: an in vitro Study.

Statement of the Problem: Continuous use of chemical agents to reduce the number of cariogenic bacteria leads to adverse effects; therefore, in recent years, many studies have focused on plant-based substances. Purpose: This study explores the antibacterial effects of Mentha Longifolia (M. longifolia) essential oil on Streptococcus mutans (S. mutans), Streptococcus sobrinus (S. sobrinus), and Lactobacillus as cariogenic microorganisms and determines the compounds in it. Materials and Method: In this experimental study, S. mutans, S. sobrinus, and Lactobacillus isolates were collected from the saliva samples of five children with severe early childhood caries (S-ECC). The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of M. longifolia essential oil were determined by Broth microdilution method. Chlorhexidine 0.2% and phosphate-buffered normal saline (pH= 7.0) were used as positive and negative controls, respectively. The chemical composition of M. longifolia essential oil was evaluated by gas chromatography-mass spectrometry. The data were analyzed with a paired t-test and the p below 0.05 was considered significant. Results: The MIC and MBC ratios for S. mutans were 3.12% and 6.25%, for S. sobrinus were 6.25% and 12.5%, ​​and Lactobacillus were 3.12% and 6.25%, respectively. Chemical analysis of M. longifolia essential oil showed that 34 various compounds. Piperitone oxide (27.59%), Transcariophylline (14.55%), and 2-cyclohexane-1-one (12.24%) were the major constituents. Conclusion: M. longifolia essential oil has both growth inhibitory and bactericidal effects on all the three species of bacteria. This antibacterial effect was similar against S. mutans and Lactobacillus, which was greater than S. sobrinus, thus, it can be used as a supplementary for caries prevention compounds.

Interaction of quercetin and 5-fluorouracil: cellular and pharmacokinetic study.

5-fluorouracil (5-FU) is a widely used chemotherapeutic agent, and its uncontrolled blood levels contribute to toxicity. Quercetin, as an important flavonoid, has many biological effects, including anti-tumor and anti-inflammatory features. The current study investigated the synergistic effect between 5-FU and quercetin using HT-29 cell line and fibroblast cells. Rats were assigned to two groups. The 5-FU/quercetin group received intraperitoneal quercetin (10 mg/kg) and the Tween was injected to the control group for 14 consecutive days. On the 15th day, both groups received 50 mg/kg of 5-FU. Upon the final injection, blood samples were obtained at different times. Pharmacokinetic parameters were evaluated using high-performance liquid chromatography (HPLC). The mean (±SD) of maximum plasma concentration (Cmax) of 5-FU in combination therapy group was 3.10 ± 0.18 µg/ml and the area under the curve (AUC) was 153.89 ± 21.36, which increased by 113% and 128% compared to control group, respectively. Quercetin increased anti-tumor activity of 5-FU and enhanced Cmax and AUC of 5-FU. These findings confirm the synergistic effects between quercetin and 5-FU at the usual doses in cancer treatment, which may lead to reduced toxicity.

Effect of thymoquinone on pharmacokinetics of 5-fluorouracil in rats and its effect on human cell line in vitro.

Thymoquinone (TQ) is one of the components extracted from Nigella sativa seeds and has antioxidant, anti-inflammatory, and anticancer effects. We evaluated the effect of TQ on 5-fluorouracil (5-FU) pharmacokinetics (PK) in vivo and in vitro on human colorectal cancer cell line. Ten Adult male Wistar rats were assigned to two groups. TQ treated group received intraperitoneal TQ once daily for 14 consecutive days (5 mg/kg). Both groups received intraperitoneal 5-FU (50 mg/kg) on day 15 and blood samples were collected from retro-orbital plexus. The pharmacokinetics parameters were analyzed using high-performance liquid chromatography (HPLC). Moreover, various concentrations of 5-FU, TQ, and combination of 5-FU and TQ were added to the HT-29 cell line and cell viability was measured using 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay. The maximum serum concentration (Cmax), area under the curve (AUC), and time of maximum concentration (Tmax) of 5-FU in TQ treated group were significantly increased approximately by 61, 60, and 24% compared to the control group, respectively. The combination of 5-FU with TQ (0.284 mM) showed a greater inhibitory effect on HT-29 cell growth compared to the alone 5-FU (0.027 and 0.055 mM) administration. TQ increases the AUC, Cmax, and Tmax of 5-FU and has a synergistic effect on the PK of 5-FU. Moreover, low concentration of TQ enhances the inhibitory effects of 5-FU on cell growth in colorectal cancer cell line. This synergistic effect might enhance the anticancer effects of low concentration of 5-FU, leading to drug dose reduction and reduced systemic toxicity of this chemotherapeutic agent.

Synthesis and characterization of a calcium phosphate bone cement with quercetin-containing PEEK/PLGA microparticles.

This study aimed to describe the synthesis and characterization of a calcium phosphate cement (CPC) with polyetheretherketone/poly (lactic-co-glycolic) acid (PEEK/PLGA) micro-particles containing quercetin. CPC powder was synthesized by mixing dicalcium phosphate anhydrate and tetracalcium phosphate. To synthesize PEEK/PLGA microparticles, PLGA85:15 was mixed with 90 wt% PEEK. The weight ratio of quercetin/PLGA/PEEK was 1:9:90 wt%. PEEK/PLGA/quercetin microparticles with 3, 5, and 6 wt% was added to CPC. The setting time, compressive strength, drug release profile, solubility, pH, and porosity of synthesized cement were evaluated. The morphology and physicochemical properties of particles was analyzed by scanning electron microscopy, Fourier-transform infrared spectroscopy (FTIR), x-ray diffraction (XRD), and inductively coupled plasma. Cytotoxicity was assessed by the methyl thiazolyl tetrazolium assay using dental pulp stem cells. Expression of osteoblastic differentiation genes was evaluated by real-time polymerase chain reaction. Data were analyzed by one-way ANOVA and Tukey's test (alpha = 0.05). The setting time of 3 wt% CPC was significantly longer than 5 and 6 wt% CPC (P< 0.001). The 6 wt% CPC had significantly higher compressive strength than other groups (P= 0.001). The release of quercetin from CPCs increased for 5 d, and then reached a plateau. XRD and FTIR confirmed the presence of hydroxyapatite in cement composition. Significantly higher expression of osteocalcin (OCN) and osteopontin (OPN) was noted in 3 wt% and 6 wt% CPCs. Addition of quercetin-containing PEEK/PLGA microparticles to CPC enhanced its compressive strength, decreased its setting time, enabled controlled drug release, and up-regulated OPN and OCN.

Antioxidant and Anticancer Potentials of the Olive and Sesame Mixture against Dimethylhydrazine-Induced Colorectal Cancer in Wistar Rats.

Cancer is one of the leading causes of death worldwide, and natural agents have shown some promise in fighting it. Thus, the present study tried to evaluate the healing potential of an equal combination of olive and sesame extract (MOS) against the colorectal cancerous lesions that were induced by dimethylhydrazine (DMH) in male rats and also compare the anticarcinogenic potential of the MOS and vitamin E with each other. Therefore, the mixture of equal olive and sesame extract (MOS) was used as the main treatment, alongside vitamin E as a parallel treatment. This study examined the red blood cell (RBC) and white blood cell (WBC) levels, biochemical indices, lactate dehydrogenase (LDH), C-reactive protein (CRP), total protein (TP), creatine kinase (CPK), albumin, and the colon tissue pathology, as well as the level of protein expression of the adenomatous polyposis coli (APC), proliferating cell nuclear antigen (PCNA), carcinoembryonic antigen (CEA), and platelet-derived growth factor (PDGF). Also, the tissue stress markers including total antioxidant capacity (TAC), malondialdehyde (MDA), and superoxide dismutase (SOD) were analyzed. Overall, the results represented a significant reduction in the congestion, mitotic index, inflammation, and cell destruction in the MOS group compared to the DMH group. In terms of the oxidative stress level, a significant increase was observed in the DMH group in comparison with the DMH-MOS group (P < 0.05), and the MOS significantly increased TAC level (P < 0.05). Furthermore, the DMH+MOS-exposed group exhibited a significantly lower expression of the PCNA, CEA, and PDGF proteins than those of the DMH group. Overall, the MOS showed that it can effectively prevent DMH-induced colon lesions. This mixture, as a strong antioxidant agent, can be clinically applied for preventing and treating colorectal cancer, the effectiveness of which is higher than that of vitamin E.

Effect of Ketorolac on Pharmacokinetics and Pharmacodynamics of 5-Fluorouracil: In Vivo and In Vitro Study.

Background: This study aimed to evaluate the impact of ketorolac on the pharmacokinetics of 5-FU and its effect on the efficacy of 5-fluorouracil (5-FU) on the HT-29 cell line. Methods: Cell culture: the HT-29 cell line was treated with different concentrations of 5-FU, ketorolac, and combination of 5-FU and ketorolac for 24 and 48 hours. The cell viability (%) was calculated by the MTT assay. Animal study: rats were randomly divided into control and pretreatment groups. The control group received physiological saline, whereas the pretreatment group received ketorolac by intraperitoneal (i.p.) injections on a daily basis for 14 days. On the 15th day, both groups received 5-FU (i.p.). Blood samples were collected at different times for HPLC analysis, and 5-FU pharmacokinetic parameters were calculated. Results: At cell culture study, in a certain concentration range, combination therapy showed synergistic effects (<0.05). However, at concentrations above this range, combination therapy showed antagonistic effects on 5-FU efficacy (<0.05). According to the pharmacokinetic analysis, pretreatment with ketorolac resulted in a significant increase in AUC, C max, and T max of 5-FU (<0.05) and a significant decrease in V/F and Cl/F of 5-FU (<0.05). Conclusions: Combination therapy with ketorolac and 5-FU, depending on time and concentration, has a synergistic effect on reducing the viability of cancer cells. Also, ketorolac is able to alter the pharmacokinetics of 5-FU. Since there is a close relationship between pharmacokinetic parameters of 5-FU and its effectiveness/toxicity, it seems that these changes are towards creating a synergistic effect on 5-FU cytotoxicity. These results suggest the need to optimize the dose of these drugs in order to increase clinical efficacy and reduce the toxicity associated with them.