Ameliorative effect of Melatonin on 5-Fluorouracil-induced reproductive toxicity in male rats.

5-Fluorouracil (5-FU) is an antimetabolite chemotherapeutic agent that can cause oxidative stress and complications in normal organs, including the reproductive system. This study was conducted to investigate the effect of melatonin (MEL) on 5-FU-induced reproductive toxicity in male rats. Male Wistar rats weighing 180 ± 20 g were divided into five groups: control, 5-FU (50 mg/kg), 5-FU + MEL (2.5, 5 & 10 mg/kg). The testes and prostates were removed, and histopathological aspects, biochemical markers, and gene expression were investigated. The effect of 5-FU on the normal TM4 cell line (murine testicular Sertoli line) and co-treatment of 5-FU and MEL were studied using MTT assay. Results showed that MEL prevented cell death in the TM4 cell line induced by 5-FU. MEL also reduced edema, hyperemia, and vacuolization in testis and prostate tissues induced by 5-FU. Additionally, MEL increased the activity of antioxidant enzymes and reduced the levels of MDA (p < 0.0001) and MPO (p < 0.0001). The levels of testosterone (p < 0.01) and the number of spermatocytes and spermatogonia (p < 0.0001) were increased in groups receiving 5-FU with MEL compared to 5-FU alone. The prostate-specific antigen (PSA) level in prostate samples was lower in the groups receiving 5-FU with MEL compared to the 5-FU group. Furthermore, the genes expression of COX-2 and TNF-α in testis tissues was reduced in the presence of MEL. in conclusion, the antioxidant property of MEL can protect the male reproductive system against 5-FU toxicity, as evidenced by the improved histopathological and biochemical parameters, as well as the reduced gene expression of COX-2 and TNF- α genes.

Unveiling the Antibacterial Properties of Statins: An In Vitro Study on Helicobacter pylori.

Background: Helicobacter pylori (H. pylori), a widespread bacterial pathogen, is associated with various gastrointestinal diseases, including gastric cancer. Statins, widely prescribed cholesterol-lowering agents, have demonstrated pleiotropic effects, including potential antimicrobial properties. This in vitro study investigated the direct antibacterial effects of three clinically approved statins, simvastatin, atorvastatin, and rosuvastatin, against H. pylori isolates. Methods: H. pylori strains were isolated from gastric biopsies of dyspeptic patients and identified by microbiological techniques. The minimum inhibitory concentrations (MICs) of statins were determined using the agar dilution method, and their antimicrobial activity was evaluated by the disc diffusion method using different concentrations of simvastatin, atorvastatin, rosuvastatin, tetracycline, and amoxicillin. Scanning electron microscopy (SEM) was employed to examine the morphology of H. pylori cells. Results: The minimum inhibitory concentration (MIC) values (µg/mL) of atorvastatin, rosuvastatin, simvastatin, tetracycline, and amoxicillin against H. pylori were 240 ± 20, 450 ± 20, 460 ± 15, 155 ± 30, and 140 ± 20, respectively. In the disc diffusion assay, atorvastatin and rosuvastatin produced significantly larger inhibition zones compared to simvastatin at all concentrations tested (p < 0.05). The inhibition zone diameters (mm) increased with higher statin concentrations, ranging from 9 ± 1.4 to 13 ± 1.4 for atorvastatin, 8 ± 0.9 to 11 ± 0.6 for rosuvastatin, and 5 ± 1.3 to 6 ± 1.4 for simvastatin at the highest tested concentration (1200 µg/ml). SEM analysis revealed the characteristic spiral morphology of H. pylori cells. Conclusion: Statins demonstrated varying degrees of antibacterial activity against H. pylori isolates, with atorvastatin exhibiting the highest potency. While the observed effects were lower than those of conventional antibiotics, these findings suggest the potential of statins as adjunctive agents or alternative therapeutic options, warranting further investigation through in vivo studies and clinical trials.

Exosomes, and the potential for exosome-based interventions against COVID-19.

Since late 2019, the world has been devastated by the coronavirus disease 2019 (COVID-19) induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with more than 760 million people affected and ∼seven million deaths reported. Although effective treatments for COVID-19 are currently limited, there has been a strong focus on developing new therapeutic approaches to address the morbidity and mortality linked to this disease. An approach that is currently being investigated is the use of exosome-based therapies. Exosomes are small, extracellular vesicles that play a role in many clinical diseases, including viral infections, infected cells release exosomes that can transmit viral components, such as miRNAs and proteins, and can also include receptors for viruses that facilitate viral entry into recipient cells. SARS-CoV-2 has the ability to impact the formation, secretion, and release of exosomes, thereby potentially facilitating or intensifying the transmission of the virus among cells, tissues and individuals. Therefore, designing synthetic exosomes that carry immunomodulatory cargo and antiviral compounds are proposed to be a promising strategy for the treatment of COVID-19 and other viral diseases. Moreover, exosomes generated from mesenchymal stem cells (MSC) might be employed as cell-free therapeutic agents, as MSC-derived exosomes can diminish the cytokine storm and reverse the suppression of host anti-viral defences associated with COVID-19, and boost the repair of lung damage linked to mitochondrial activity. The present article discusses the significance and roles of exosomes in COVID-19, and explores potential future applications of exosomes in combating this disease. Despite the challenges posed by COVID-19, exosome-based therapies could represent a promising avenue for improving patient outcomes and reducing the impact of this disease.

Distal Forearm Arteriovenous Fistula Maturation in Diabetic Hemodialysis Patients.

PURPOSE: Atherosclerotic disease of the forearm arteries can impede the maturation of distal fistulas in diabetic patients. The goal of this study was to look at the maturity of diabetic hemodialysis patients' distal forearm (radiocephalic snuffbox or distal forearm) arteriovenous fistulas. MATERIALS AND METHODS: Patients with chronic renal failure who were candidates for distal forearm radiocephalic arteriovenous fistula implantation were evaluated in this cross-sectional study. Patients' demographic details, underlying disorders, laboratory measurements, vital signs, and information on their surgery were all noted. Patients were checked for fistula development 1 week, 1 month, 2 months, and then monthly until 6 months after surgery. Arteriovenous fistula maturation characterized by optimal blood flow, vessel dilation, and structural adaptations. RESULTS: Among 343 patients (56% male, 44% female, mean age: 57.32 ± 12.48 years), hypertension prevailed (81.9%), followed by hyperlipidemia (42.3%) and coronary artery disease history (25.9%). AVFs achieved 58.3% maturation in 64.98 ± 11.05 days; higher BP during creation correlated with successful maturation (17.02 ± 1.46 mmHg vs 13.90 ± 1.93 mmHg, P < .05). No significant statistical difference found in distal forearm arteriovenous fistula maturation between males (57.8%) and females (58.9%) (P > .005). However, 41.7% of AVFs failed in 18.83 ± 17.89 days. Failed AVFs exhibited lower BP during operation and failure (11.75 ± 1.86 mmHg). Kaplan-Meier analysis depicted maturation probabilities over 90 days post-surgery. CONCLUSION: Diabetes and patient sex did not affect the maturation time of distal forearm AVFs in hemodialysis patients. Increased blood pressure during and after surgery correlated with shorter maturation time.

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.

An Update on Betrixaban, The Challenging Anticoagulant Agent for Extended Venous Thromboembolism Prophylaxis.

ABSTRACT: Venous thromboembolism (VTE) is a prevalent yet preventable cause of death, particularly among hospitalized patients. Studies have shown that the risk of VTE remains high for up to 6 months after discharge, highlighting the need for extended thromboprophylaxis as a viable treatment approach. Despite the availability of several anticoagulant drugs such as vitamin K antagonists, heparinoids, rivaroxaban, apixaban, edoxaban, and dabigatran, none of them has received approval from the US Food and Drug Administration for long-term thromboprophylaxis. However, an emerging factor Xa inhibitor called betrixaban has shown promising results in Phase II and phase III trials, positioning itself as the first and only US Food and Drug Administration-approved anticoagulant for extended thromboprophylaxis in hospitalized patients after discharge. Betrixaban offers distinct pharmacological characteristics, including a long half-life, low renal excretion, and unique hepatic metabolism, making it an attractive option for various theoretical uses. Numerous articles have been published discussing the safety and efficacy of betrixaban, all of which have emphasized its usefulness and practicality. However, there has been limited discussion regarding its weaknesses and areas of ambiguity. Therefore, this article aimed to explore the challenges faced during the approval process of betrixaban and provide a comprehensive review of the literature on its advantages and disadvantages as a long-term prophylaxis approach for VTE. Furthermore, we aim to identify the ambiguous points that require further investigation in future studies.

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.

Comparison of Aripiprazole and Risperidone effectiveness in treating obsessive-compulsive disorder in patients with bipolar disorder: Double-blind, randomized clinical trial.

Background: Obsessive-compulsive disorder (OCD) is a mental illness with a chronic coarse and waxing and waning of symptoms. Treatment of OCD in patients with bipolar disorder (BD) remains challenging. Objectives: The present study aims to compare the safety and effectiveness of Risperidone and Aripiprazole as adjunctive therapy with valproate sodium, in treating mania, depression, and OCD in patients with comorbidity of OCD-BD. Methods: This research is 3 phase, double-blind, randomized clinical trial, with a total number of 64 patients. The diagnostic psychiatrist clinical interview was based on diagnostic and statistical manual of mental disorders, 5th edition (DSM-5) criteria. For assessing severity of OCD, mania, and depression, Yale-Brown obsessive-compulsive scale (Y-BOCS), young mania rating scale (YMRS), and Hamilton depression rating scale (HAM-D) scores were used. Patients were randomly assigned to the two parallel groups. All patients in both group were received valproate sodium, one group was treated with Aripiprazole and the other group was treated with Risperidon as adjective therapy with valproate sodium.The SPSS software (version 22), χ 2 test, t-test, and analysis of variance with repeated measures were used to analyze the data. Results: The dosage and time of both drugs were statistically significant in reducing the mean score of all three mentioned scales, but the effect of group was not statistically significant in HAM-D and YMRS scores, only in terms of OCD, the mean of the Y-BOCS score was significantly lower in the Aripiprazole group (p < 0.001). In relation to side effects, Risperidone induced statistically significant weight gain (p < 0.001) and Aripiprazole induced statistically significant sleep disturbance (p < 0.05). Conclusions: Both Aripiprazole and Risperidone can be used effectively as adjunctive therapy with valproate sodium in treating OCD in patients with BD without any serious and life threatening adverse effect. Aripiprazole is more effective than Risperidone in treating OCD in BD.

Efficacy of sesame oil versus placebo in the management of acute radiation-induced dermatitis in breast cancer patients: A double-blind randomized clinical trial.

AIM: Considering the anti-inflammatory and positive effects of sesame oil in treating skin diseases, the present research aimed to study its therapeutic effects on acute radiotherapy dermatitis in such patients. METHODS: Forty women with breast cancer during radiotherapy (for 5 weeks) were randomly grouped into two categories: sesame oil (20 patients) and placebo (20 patients). After each radiotherapy session, they were asked to use 3cc of the ointment on the treating field and continue the treatment until the end. They were examined weekly according to the staging criteria of the radiation therapy oncology group. RESULTS: No significant difference was observed in the first 3 weeks. In the fourth week, dermatitis grade 0 was 35%, grade 1 was 65%, and grade 2 was 0% in the intervention (case) group, while in the control group, they were 10%, 75%, and 15%, respectively. This difference was statistically significant (p = 0.046). Also, in the fifth week in the case group, dermatitis grade 0 was 25%, grade 1 was 70%, and grade 2 was 5%, while in the control group, they were 0%, 80%, and 20%, respectively. This difference was also statistically significant (p = 0.032). CONCLUSION: Based on the findings, sesame oil, as a cheap and available herbal treatment, may be utilized in treating acute dermatitis caused by radiotherapy. However, an investigation with a larger sample size in several centers should be conducted to examine sesame oil effects in treating acute radio dermatitis more comprehensively.

Fabrication of an ultra-sensitive electrochemical DNA biosensor based on CT-DNA/NiFe2O4NPs/Au/CPE for detecting rizatriptan benzoate.

A novel and first electrochemical biosensor based on Deoxyribonucleic acid (DNA) as a biological component to measure an antimigraine drug, rizatriptan benzoate (RZB) for patients under treatment in biological samples was developed. A carbon paste electrode (CPE) was modified by calf thymus (CT) double-stranded (ds)-DNA, nickel ferrite magnetic nanoparticles (NiFe2O4NPs), and gold nanoparticles (AuNPs). The morphology of the CT-DNA/NiFe2O4NPs/AuNPs/CPE was characterized by Field emission scanning electron microscope (FESEM). The presence of NiFe2O4NPs and AuNPs was confirmed by energy-dispersive X-ray spectroscopy (EDS) image of the NiFe2O4NPs/AuNPs/CPE surface. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) were used to determine the structure and electrochemical characteristics of the CT-DNA/NiFe2O4NPs/AuNPs/CPE. Differential pulse voltammetry (DPV) was used to investigate the electrochemical behavior of RZB. Chronoamperometry (CA) was applied to study the effect of CT-DNA immobilization time on the peak oxidation current of RZB accumulated on the surface of the CT-DNA/NiFe2O4NPs/AuNPs/CPE. The results showed that, under optimum conditions, the prepared electrode responded linearly to RZB concentrations between 0.01 and 2.0 µM, with a 0.0033 µM detection limit (LOD) and 0.01 µM limit of quantification (LOQ). The parameters influencing the biosensor performance (temperature, CT-DNA immobilization time, and RZB/CT-DNA accumulation time) were optimized. DPV showed the displacement of the peak potential towards positive values and the reduction of its current, indicating that the drug could intercalate between the guanine base pairs of CT-DNA. Our biosensor was successfully applied for RZB measurement in human urine, blood serum, plasma samples, and tablets. The presented biosensor was fast response, sensitive, selective, cost-effective, and easy-to-use for RZB determination in pharmaceutical formulations and biological samples.

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.

Design, synthesis, in vitro anti-α-glucosidase evaluations, and computational studies of new phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides as potential anti-diabetic agents.

An important target in the treatment of type 2 diabetes is α-glucosidase. Inhibition of this enzyme led to delay in glucose absorption and decrease in postprandial hyperglycemia. A new series of phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides 11a-n were designed based on the reported potent α-glucosidase inhibitors. These compounds were synthesized and screened for their in vitro inhibitory activity against the latter enzyme. The majority of the evaluated compounds displayed high inhibition effects (IC50 values in the range of 45.26 ± 0.03-491.68 ± 0.11 µM) as compared to the positive control acarbose (IC50 value = 750.1 ± 0.23 µM). Among this series, compounds 11j and 11i represented the most potent α-glucosidase inhibitory activities with IC50 values of 45.26 ± 0.03 and 46.25 ± 0.89 µM. Kinetic analysis revealed that the compound 11j is a competitive inhibitor with a Ki of 50.4 µM. Furthermore, the binding interactions of the most potent compounds in α-glucosidase active site were studied through molecular docking and molecular dynamics. The latter studies confirmed the obtained results through in vitro experiments. Furthermore, in silico pharmacokinetic study of the most potent compounds was also performed.

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.

N-Acetylcysteine attenuated pulmonary fibrosis induced by bleomycin via immunomodulation responses.

Background and purpose: Pulmonary fibrosis (PF) is a chronic and life-threatening interstitial lung disease. N-acetyl cysteine (NAC) is an antioxidant pharmaceutically available to reduce endothelial dysfunction, inflammation, and fibrosis, however, the therapeutic effect of NAC on PF has not been clearly identified. This research aimed to investigate the possible therapeutic impact of NAC on PF induced by bleomycin in the rat model. Experimental approach: Rats received intraperitoneal injections of NAC at 150, 300, and 600 mg/kg for 28 days before bleomycin, while the positive and negative control groups were treated with bleomycin alone and normal saline, respectively. Then, rats' lung tissues were isolated and leukocyte infiltration and also collagen deposition were evaluated using hematoxylin and eosin and Mallory trichrome stainings, respectively. In addition, the levels of IL-17, and TGF-ß cytokines in bronchoalveolar lavage fluid and hydroxyproline in homogenized lung tissues were assayed using the ELISA method. Findings/Results: Histological findings indicated that NAC decreased leukocyte infiltration, collagen deposition, and fibrosis score in the bleomycin-induced PF tissue. Moreover, NAC significantly reduced TGF-ß and hydroxyproline levels at 300-600 mg/kg, as well as IL-17 cytokine at 600 mg/kg. Conclusion and implications: NAC showed a potential anti-fibrotic effect by reducing hydroxyproline and TGF-ß as well as an anti-inflammatory effect by decreasing IL-17 cytokine. So, it may be administered as a prophylactic or therapeutic candidate agent to attenuate PF via immunomodulatory effects. Although, future studies are suggested.

Virtual screening reveals aprepitant to be a potent inhibitor of neutral sphingomyelinase 2: implications in blockade of exosome release in cancer therapy.

PURPOSE: Exosomes are membrane-derived nano-vesicles upregulated in pathological conditions like cancer. Therefore, inhibiting their release is a potential strategy for the development of more efficient combination therapies. Neutral sphingomyelinase 2 (nSMase2) is a key component in exosome release; however, a clinically safe yet efficient nSMase2 inhibitor remains to be used discovered. Accordingly, we made an effort to identify potential nSMase2 inhibitor(s) among the approved drugs. METHODS: Virtual screening was performed and aprepitant was selected for further investigation. To evaluate the reliability of the complex, molecular dynamics were performed. Finally, using the CCK-8 assay in HCT116 cells, the highest non-toxic concentrations of aprepitant were identified and the nSMase2 activity assay was performed to measure the inhibitory activity of aprepitant, in vitro. RESULTS: To validate the screening results, molecular docking was performed, and the retrieved scores were in line with the screening results. The root-mean-square deviation (RMSD) plot of aprepitant-nSMase2 showed proper convergence. Following treatment with different concentrations of aprepitant in both cell-free and cell-dependent assays, nSMase2 activity was remarkably decreased. CONCLUSION: Aprepitant, at a concentration as low as 15 µM, was able to inhibit nSmase2 activity in HCT116 cells without any significant effects on their viability. Aprepitant is therefore suggested to be a potentially safe exosome release inhibitor.

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.