Iranian Journal of Pharmaceutical Research
Volume:20 Issue: 3, Summer 2021

A novel series of benzothiazine-3-carboxamide 1,1-dioxide derivatives by modifying the piroxicam scaffold was designed, synthesized, and evaluated as anti-HIV agents. The 1,2-benzothiazine-3-carboxamide 1,1-dioxide scaffold consists of hydroxy and carboxamide groups as a chelating motif to form an interaction with Mg2+ ions within the integrase active site as a target. Most of the compounds displayed encouraging anti-HIV activity in a cell-based assay. Among them, compounds 13d, 13l and 13m were the most potent with EC50 values ranging from 20-25 mM and SI > 26. Docking study of compounds in integrase active site proposed that the mechanism of action of compounds might be through Mg2+ chelation within integrase active site. The lack of severe cytotoxicity and favorable anti-HIV activity of benzothiazine-3-carboxamide 1,1-dioxide derivatives support further modifications to improve the potency.

Dendrobium huoshanense (DHS) has long been used to make tea drink, soup, and porridge to protect eye and liver in many Southeast Asian countries for centuries. As a rare and endangered functional food, adulteration in DHS with visually similar but cheaper and more accessible plants such as Dendrobium henanense (DHN) because of their similarities in morphology has become prevalent in the market. In this study, the Attenuated Total Reflectance Fourier transform Infrared Spectroscopy (ATR-FTIR) combined with chemometric methods was established to detect fraudulent addition in DHS with DHN. The partial least squares (PLS) models based on the ATR-FTIR files of DHS mixed with different proportions of DHN were built under cross validation and tested with different independent data sets. To reduce the variables' lack of information and increase the accuracy of the model, different wavelength selection methods including Moving Window Partial Least Squares (MW-PLS), Monte Carlo-uninformative variable elimination (MC-UVE), and interval random frog (iRF) were compared.The results showed that iRF performed the most perfectly with the number of latent variables (nLVs = 7), the lowest Root Mean Square Error of Cross-Validation (RMSECV = 7.37), and the maximum determination coefficients (R2 = 0.9721). The excellent performance of the model was proved by the low RMSEP value of 6.44% and the high R2 value of 0.9556. The developed method could rapidly quantify the adulteration DHN in DHS, and our study might provide an efficient and great potential technique tool for the rapid, green, low-cost, and nondestructive identification and quantification for DHS adulterated with DHN.

A key element in therapeutic communication is trust and it needs to be created and maintained between health care providers and recipients reciprocally. This study aimed to identify the factors that can enhance and improve trust between pharmacists and patients. This study was a qualitative study consisting of an in-depth semi-structured interview followed by a focus group discussion. In the first phase of the study, a semi-structured open-ended interview was conducted with patients, pharmacists, and pharmacy technicians. The interview phase was followed by transcribing verbatim and content analysis and a focus group discussion. Finally, 49 items of trust-building factors between the patient and the pharmacists were obtained. A questionnaire was designed and distributed among 80 people for transparency and relevance, similar to the participants. The necessary corrections and changes were made in the items after collecting the answers. The study achieved two main themes; external and internal trust-building factors. Internal factors include the category of the factors related to human resources and managerial factors. Finally, 49 trust-building factors were developed. Internal factors are those factors in which the pharmacist, the pharmacy technician, and the pharmacy's management system play a key role in building trust between pharmacists and patients.

The aim of this study was to assess the occurrence of Aflatoxins (AFs) including B1, B2, G1 and G2 in commercial cereal-based baby foods by HPLC-FLD method in Iran and related risk assessment in three baby age groups (6-12, 12-18, and 18-24 months) using Monte Carlo simulation approach. Results showed an occurrence ranging from 20% to 60% for B1, B2, and G2 aflatoxins, while AFG1 was not detected in any assessed samples. Exposure and risk assessment was estimated to be two groups (aflatoxin B1 and total aflatoxins). The highest estimated dietary exposure to both AFB1 and total AFs was estimated for 6-12 months aged babies, representing 5.81 ng/kg BW/day and 8.55 ng/kg BW/day, respectively. Overall, the margin of exposures to AFB1 and total AFs were lower than 10,000 in all age groups, indicating a health concern about AFB1 and total AFs exposure through cereal-based baby food consumption. High cancer risk for high consumers (P95) of baby food was also estimated in all age groups, calling for immediate intervention due to serious claims that AFB1, is a highly carcinogenic component, causes hepatocellular carcinoma. Risk ranking results indicated the presence of AFB1 is classified as high risk for babies who consume cereal-based foods, which demands the attention of risk managers to reduce or eliminate this risk for the most vulnerable sector of society, whose aged <24 months.

Antipyretic acetaminophen (APAP) is a commonly used drug that generally associates with liver injury. (-)-Epigallocatechin-3-gallate (EGCG), an active polyphenol extracted from green tea, is extensively reported to have the potential to impact a variety of human diseases. However, few studies were reported regarding the protective effect of EGCG on APAP-induced liver injury and the mechanism is still unclear. In this study, in-vitro and in-vivo experiments were carried out to verify the hepatoprotective effect of EGCG against APAP-induced liver injury and explore the potential mechanism. Results indicated that EGCG effectively relieved the liver injury caused by APAP, as well as APAP-induced mitochondrial dysfunction. The protective role of EGCG was not only attributed to its antioxidant capacity; but also might be related to the protective effect on hepatic mitochondrial impairment; based on that, EGCG could improve the membrane potential and activities of the respiratory chain complexes in liver mitochondria. Our study casts a new light on the mechanism of EGCG's hepatoprotective effect and suggests that EGCG has considerable potential in developing tonics for relieving APAP-induced liver injury.

There is no currently successful method to treat Covid-19 infection. Nevertheless, previously licensed pharmaceuticals to treat other virus infections are used on an off-label basis either alone or in combination. One of them is favipiravir. Favipiravir, also known as favilavir, is an antiviral drug that is active against many viruses. Spectrophotometric and liquid chromatographic methods have been developed and validated for the quantitative determination of favipiravir in pharmaceutical formulations. Chromatographic method has been performed using reverse-phase technique on a C-18 column with a mobile phase consisting of sodium acetate solution (pH adjusted to 3.0 with glacial acetic acid) and acetonitrile (85:15, v/v) at 30 oC. The mobile phase flow rate was 1.0 mL min-1. For the determination of favipiravir, UV spectrum has been recorded between 200 and 800 nm using deionized water as solvent and the wavelength of 227 nm has been selected. Both methods have been validated in terms of their specificity, linearity, limits of detection and quantification, precision, accuracy, and robustness. Both methods have demonstrated good linearity, precision and recovery. No spectral and chromatographic interferences from the tablet excipients were found in spectrophotometric and liquid chromatographic methods. In both methods, correlation coefficients were greater than 0.999 within a concentration range of 10–60 mg mL-1 using spectrophotometry and chromatography. Intra-day and inter-day precision were observed with low relative standard deviation values. The accuracy of the methods were within the range 99.57-100.10% for LC and from 99.83–100.45% for UV. Therefore, both methods gave the most reliable outcomes for the determination of favipiravir in pharmaceutical formulation.

< p>Coronavirus disease 2019 (COVID-19) management in patients with predisposing psychiatric disorders would be challenging due to potential drug-drug interactions (PDDIs) and precipitation of their disease severity. Furthermore, COVID-19 itself might precipitate or induce unpredicted psychiatry and neuropsychiatry complications in these patients. In this literature review study, the psychological impacts of COVID-19 and major psychiatric adverse drug reactions (ADRs) of COVID-19 treatment options have been discussed. A detailed Table has been provided to assess potential drug-drug interactions of COVID-19 treatment options with psychotropic medications to avoid unwanted major drug-drug interactions. Finally, potential mechanisms of these major drug-drug interactions and possible management of them have been summarized. The most common type of major PDDIs is pharmacokinetics. Hydroxychloroquine/chloroquine and lopinavir/ritonavir were the most involved anti-COVID-19 agents in these major PDDIs.

The research aims to develop bionanosuspension using a biopolymer isolated from Fragaria ananassa fruit that constitutes potential and natural polymeric properties. At first, the biomaterial was isolated from the natural fruit pulp of Fragaria ananassa by an economical method of isolation. The model drug was nanosized by a novel sonication method. The isolated biopolymer was characterized for its polymeric properties, and its potential capabilities were evaluated in the delivery of nanosized phenytoin. The isolated biopolymer was characterized for DSC, FTIR, NMR, mass, and scanning electron microscopy. The isolated biomaterial was used for the preparation of phenytoin-loaded bionanosuspension with other excipients. The bionanoparticles were also characterized by different analytical testing such as FTIR, DSC, and SEM to confirm any interaction between model drug and biopolymer. The prepared bionanoparticles showed the release of phenytoin in a sustained manner over 36 hours. The release kinetic study was done using the BIT-SOFT 1.12 software and other parameters such as t50%, t80%, and r2 were calculated. The formulation PFr6 was considered best having t50% in 18.22 hours and t80% in 29.62 h with an r2 value of 0.9793. This formulation showed up to 87.89% drug release within 36 hours. The prepared bio-nanosuspension was found to be stable and in a well-dispersed state. The dried bionanosuspension evaluation revealed no interaction between model drug and biopolymer without any loss of characteristic peaks. Therefore, the isolated biopolymer can be safely used to prepare stable bionanosuspension loaded with nanosized phenytoin.

Pharmaceutical productions are recognized as an essential commodity in the economical literature; therefore, an increase in their prices leads to an increase in the household budget. Currently, about 15-20% of the entire health expenditure in Iran is allocated to the pharmaceutical sector. This study aimed to investigate the effect of inflation and its uncertainty on inflation in pharmaceutical prices in Iran. In this study, the monthly time series of consumer price index from 2001 to 2017 was used to calculate inflation uncertainty based on a generalized autoregressive conditional heteroscedasticity model. Hylleberg-Engle-Granger-Yoo test was performed to determine the stationary of the data. Feasibility tests were also used to explore the application of Autoregressive conditional heteroscedasticity family models to these data. The causal relationship between inflation uncertainty and inflation in the pharmaceutical sector was investigated using the Granger causality test. A causal relationship was found between inflation and inflation uncertainty at the 95% confidence interval for the monthly data during the study. It was revealed that Inflation uncertainty did not affect the inflation in the pharmaceutical prices, but inflation can be a cause of pharmaceutical inflation. Although inflation uncertainty has no association with pharmaceutical inflation, it seems that it could affect pharmaceutical inflation through inflation in other sectors. Therefore, adopting appropriate monetary policies aimed at controlling liquidity and inflation can effectively control pharmaceutical prices.

Melatonin is the "clock factor" produced from the pineal gland dominating regular circadian rhythm in mammalians. It is an indoleamine with potent multifunctional pharmacological effects, both receptor dependent and non-receptor dependent effects, including antioxidant and anti-inflammatory activities. The aim of this review is to summarize clinical evidence related to melatonin's effectiveness in the treatment of liver and pancreas diseases. Databases including PubMed, Scopus, and Cochran Library were searched up to November 2020.Finally, this review has summarized up-to-date clinical evidence to investigate the efficacy and safety of melatonin for the management of liver and pancreas diseases. Melatonin has been demonstrated to have beneficial effects on the management of Non-alcoholic fatty liver disease (NAFLD), sleep disturbance of cirrhotic patients, prevention of drug/poison induced liver toxicity,and prevention of post endoscopic retrograde cholangiopancreatography pancreatitis (PEP);more data is needed to recommend melatonin administration in the treatment of mentioned disorders.

Volatile organic compositions of the essential oils (EOs), solid-phase microextraction (SPME) and SPME of n-hexane extracts from the flower and stem-leaf of Filipendula vulgaris (F. vulgaris) were analyzed by GC-FID/MS.  A total of 107 constituents were characterized, flower and stem-leaf parts of the plant were found to contain different volatile organic compounds. Tricosane (29.6%), n-nonanal (20.5%) were identified as the main components in the essential oil of the flower, while phytol  (35.2%) was found to be a major constituent in the essential oil of stem-leaf. Benzaldehyde (56.0%) and n-nonanal (31.6%) were the major groups in the SPME of stem-leaf and flower, respectively. The volatiles for the SPME of n-hexane extracts of the flower and stem-leaf of F. vulgaris were predominated by aromatic compounds (75.0% and 78.5%) and ketones (18.1% and 10.1%), respectively. On the other hand, a total of terpene compounds was found at the most in the EO of the stem-leaf part of the plant (48.6%). In addition, antimicrobial, tyrosinase inhibition, and nitric oxide scavenging activities of the n-hexane (H), methanol (M), aqueous extracts (A) and EOs of F. vulgaris were investigated. EOs and methanol extracts of flower and stem-leaf had high antimicrobial activity against tested various microorganisms. However, n-hexane extracts of the flower and stem-leaf only displayed activity againstMycobacterium smegmatis. Methanol extracts of flower and stem-leaf possessed the best tyrosine inhibition and NO scavenging activity.

Rho-associated kinases (ROCK) are a class of serine/threonine kinases that play important roles in various biological processes. ROCK are becoming attractive targets for drug designing. A novel scaffold was designed according to molecular hybridization strategy, then a series of 4-aryl-5-aminomethyl-thiazole-2-amines were synthesized, and their inhibitory activities on ROCK were screened by enzyme-linked immunosorbent assay (ELISA). The results showed that 4-aryl-5-aminomethyl-thiazole-2-amines derivatives displayed certain ROCK II inhibitory activities. The IC50 value of the most potent compound 4v was found to be 20 nM. The preliminary structure-activity-relationship investigation showed that compounds with 4-pyridine substitution were generally found to be more potent than compounds with 3-pyridine substitution. The molecular docking studies indicated that more optimization work needs to conduct to obtain more potent ROCK inhibitors.

To analyze the effect, side effects, and satisfaction of the second-generation radiopaque subcutaneous implant, providing healthcare workers a basis for propaganda and guidance. Methods A total of 214 cases of healthy women with birth control requirements from August 2016 to June 2018 received ray subcutaneous implants. Quantitative surveys were administered 10 days, 3 months, 12 months, and 24 months later. All cases were implanted successfully. The number of effective cases was 211, with 3 cases lost to follow-up. The pregnancy rate of 211 subjects during receiving implant was 0. Changes in bleeding patterns (130 cases, 61.61%) remained the most common side effect event. The rate of withdrawal was 96.21% in the first year and 66.35% in the second year. There were 48 cases (67.61%) who withdrew due to the change of bleeding pattern. All participants with bleeding patterns were divided into the withdrawal group and the non-withdrawal group, and there were significant differences in educational background, number of pregnancies, abortion, and income between the two groups. According to the satisfaction survey, 37 (17.54%) were very satisfied, 109 (51.66%) were satisfied. The contraceptive rate of radiopaque subcutaneous implantation was very high, and there were no serious side effects while receiving an implant. The change of bleeding pattern was the main reason for withdrawal, which was related to educational background, number of pregnancies, history of abortion, and economic conditions. Pre-implantation consultation and post-implantation management should be strengthened.

This research aimed to evaluate the cytotoxicity, anti-bacterial, anti-fungal and heme polymerization inhibition activities, as well as the detection of the chemical composition of essential oils and measurement of the amount of total phenol and flavonoids of Cousinia harazensis and C. calocephala. In-vitro growth inhibitory effects of methanol extracts on A2780, T-47D, A549 and Hep-G2 cells were evaluated by MTT assay. MIC and MBC/MFC were determined by the agar dilution method. The anti-malarial activity of herbs was assessed with an inhibition test of heme detoxification (ITHD). Total phenol and flavonoids content measured by Folin-Ciocalteu method. The essential oils from two herbs were extracted by hydro-distillation, and GC/MS analyzed their compositions. Cell studies against selected cell lines growth in MTT assay were related to C. harazensis on Hep-G2 with IC50 of 4.521 µg/mL. The MIC of anti-bacterial and anti-fungal effects is related to C. harazensis extract on Staphylococcus epidermidis and Aspergillus fumigatus with 15.62 and 62.5 mg/mL, respectively. Both extracts do not have anti-malarial activity. C. harzensis content was richer in total phenol and flavonoids rather than the other herb. m-benzyl benzyl alcohol (46.7%) and butyl phthalate (14.7%) are the major compounds of C. harazensis; main components of C. calocephala are 3-methyl-tetrahydrofuran (24.6%) and oleic acid (15.4%). In conclusion, C. harazensis with more phenol and flavonoids content showed better results in terms of biological activities.

An important challenge in neurobiology is to stimulate a single neuron, especially in deep areas of the brain. The optogenetics methods need a surgical operation to convey light sources to targeted cells. Nowadays, non-invasive tools such as sonogenetics with the ability to modulate and visualizing cellular and molecular processes have attracted much attention. The study of the biological functions of living organisms always requires tools for monitoring and imaging dynamically. Current sonogenetic approaches use ultrasound as a non-invasive tool to precisely control cellular function. In general, sonogenetics includes the development of mechano-sensitive proteins, approaches for introducing their genes to specific cells, targeted stimulation, and finally, reading the outcome. Hence, to prepare a short review of emerging technology sonogenetics, we summarized the introduction of sound waves, the mechano-sensitive proteins commonly used in sonogenetics, and potential therapeutic applications of sonogenetics for biological research and medicine. This short review would beneficiate in the translation of sonogenetics from present in-vitro and in-vivo investigations to clinical therapies.

Novel phenanthro-triazine-3-thiol derivatives were designed as potential DNA intercalators and Bcl-2 inhibitors. After being synthesized, the compounds were evaluated for their cytotoxic activity against MOLT-4 (human acute lymphoblastic leukemia) and MCF-7 (human breast adenocarcinoma) cells by MTT assay. P1 (bearing hydrogen substitution) was the most potent derivative against MOLT-4 with an IC50 value of 7.1 ± 1.1 μM, whereas P11 (bearing phenyl substitution) demonstrated considerable cytotoxicity against MCF-7 with an IC50 value of 15.4 ± 2.9 μM. Compounds P7, P8, P14 and P15 exhibited moderate cytotoxic effects. Furthermore, to confirm the potential DNA intercalation and Bcl-2 inhibitory activities of phenanthro-triazine scaffolds, molecular docking analysis was performed. Molecular docking studies indicated that these compounds not only bind to DNA by intercalation mainly through stacking interactions but also are well accommodated in the active site of Bcl-2. Therefore, P1 and P11 having phenanthro-triazine-3-thiol scaffold could be presented as cytotoxic agents with dual DNA intercalation and Bcl-2 inhibitory activities.

As a common intervention among burn patients, skin graft has some risks such as infections and delay of wound healing. The aim of this study was to assess the efficacy and safety of topical 0.25% Timolol Gel (TG) in promoting wound healing in split-thickness skin graft donor sites. We conducted a double-blind, randomized clinical trial to assess re-epithelialization time, the level of pain based on the Visual Analog Scale (VAS), and the wound infection incidence. The scar status was also evaluated by the Vancouver Scar Scale (VSS) and the Patient and Observer Scar Assessment Scale (POSAS). Totally, 64 patients were randomly assigned to the study groups. The two groups showed a significant difference in healing time (14.5 ± 3.2 vs. 11.5 ± 2.3 days, P < 0.001). No infection occurred in either group, and 3 cases of transplant rejection were observed in the placebo group. The VAS was significantly different on days 1, 2, 3, 4, and 7 (P < 0.05). In the third month, the results showed a significant difference in terms of VSS (P = 0.005). Topical TG, due to its favorable effects on wound healing and pain reduction, can be administered as a therapeutic agent in patients with a skin graft.

Quantum dots (QDs) are one of the first nanotechnological materials to be integrated with sensor technologies and have been widely anticipated to eventually find application chances in several commercial pharmaceutical and clinical products. They are one of the most important developments in the rapidly growing world of material science technology. The excellent properties of QDs may allow the design of simple, precise, and inexpensive electrochemical methods for the detection of pharmaceuticals. Electrochemical techniques offer accuracy, high sensitivity, low cost, simplicity, ease of preparation of the samples in a very short time, and speed of analysis. The most commonly used voltammetric techniques are differential pulse voltammetry, cyclic voltammetry, square wave voltammetry, and stripping voltammetry. The purpose of this review is to show and communicate the advantages and uses of QD applications used in drug analysis. Besides, the present application methods of QDs to the pharmaceutical analysis and their related parameters were summarized between 2012 and 2021 years and summarized as a table.

Neuropathic pain results from trauma or diseases affecting the central nervous system (CNS) and triggers a cascade of events in different CNS parts that eventually lead to oxidative injury. This study was aimed to investigate the protective effects of some selected analgesics in neuropathic pain-induced oxidative damage in the isolated glial cells of the rat brain. In this experiment, rats were randomly divided into 5 main groups. Rats in group 1 received no medication, whereas rats in groups 2 to 5 received ASA (aspirin), celecoxib, morphine, and etanercept daily, respectively. Each main group divides into 3 subgroups: normal, sham, and neuropathic pain model rats. The glial cells of the rat brain were isolated at different time points. Our results demonstrate that neuropathic pain induces ROS generation as the major cause of mitochondrial membrane potential collapse (%∆Ψm) and lysosomal membrane rupture, which result in oxidative damage of the glial cells. In addition, ASA and celecoxib had protective effects on the neuropathic pain-induced oxidative stress markers, including ROS production, mitochondrial membrane potential collapse, and lysosomal membrane leakiness at different time points.Furthermore, the oxidative damage markers were significantly decreased by morphine and etanercept in all investigated days. Since arachidonic acid metabolites and TNF-α are produced during neuropathic pain and inflammation, it can be concluded that the inhibition of the substances production or inhibition of the ligands binding with their receptors would help to decrease the destructive effects of neuropathic pain in the glial cells of rat brain.

In patients with diuretic resistance due to heart failure, higher doses or continuous furosemide infusion and adding hypertonic saline solution (HSS) to diuretics could be effective. The goal of this study was to assess the effectiveness of hypertonic saline solution administration in weight loss of hospitalizedpatients with diuretic-resistant edema due to heart failure. In a randomized double-blinded clinical trial, adult patients with diffuse peripheral edema due to heart failure who were unresponsive to 80 mg of oral furosemide were enrolled. The patients were randomized into two groups. In the intervention and control groups, patients received 150 mL of HSS and normal saline, respectively. Subjects in both groups received 250 mg IV furosemide every 12 h for 48 h. The change in body weight, urine output, blood pressure, uric acid, urine osmolality, blood biochemistry, and urinary cystatin C levels were assessed. Based on defined inclusion and exclusion criteria, 28 patients, 14 in each group, were recruited. The groups were similar in demographic and baseline laboratory characteristics. A significant decrease in body weight was observed in the intervention group (P = 0.002). The change in other measured parameters, including urine output and urinary cystatin C levels, was not reached statistical significance. Our findings suggest that the administration of HSS as an adjunct to loop diuretics could provide a safe and effective treatment for increasing urine output and decreasing weight in patients with heart failure.

This study aimed to estimate Iranian willingness to pay (WTP) for a hypothetical COVID-19 vaccine and its determinants. A cross-sectional online survey was conducted from May 2nd to 20th, 2020 among the general population of Iran to estimate WTP for hypothetical COVID-19 vaccines. Four scenarios with different levels of efficacy and duration of protection were presented to respondents in the payment card scale of the contingent valuation method (CVM). With the corresponding WTPs under different scenarios, mean, trimmed mean, median WTP values, and vaccine demand was estimated. A semi-log regression model was employed to identify key factors. The vaccine acceptance rate and positive WTP were about 70% and 80%, respectively. The reluctant individuals believed free vaccination is a government responsibility. The highest trimmed mean and median WTP values were the US $15 and $4 for the vaccine with more than 80% efficacy and one-time vaccination. The median decreased to the US $2 in less effective scenarios. The vaccine demand was price-inelastic. Price, self-assessment virus risk, age, gender, education, income, and working in the health sector were significant factors. Given the price inelasticity of the COVID-19 vaccine, providing free vaccination by the Iranian government is highly recommended, particularly for low-income and vulnerable individuals.

This work is aimed to elucidate cytotoxic and apoptotic effects of Salvia syriaca essential oil and its chemical composition by GC-MS. The human colon cancer cells (Caco-2) were treated with different essential oil concentrations for 24 h. Crystal violet test was used to determine cell viability at 630 nm by using an ELISA reader. Apoptotic processes were measured by Annexin V-FITC Apoptosis Assay Kit. Germacrene D (21.77%), trans-β-ocimene (14.66%), β-pinene (9.07%), α-cadinol (8.19%) and α-pinene (6.50%) were the main components of oil determined by GC-MS. Moreover, we observed that the cytotoxic effect was increased with an increasing dose of essential oil. The EC50 value was calculated as 63.5 µg/mL. An increase in the percentage of apoptotic cells was observed after treatment of Caco-2 cells with S. syriaca essential oil revealed by image-based cytometry. A nearly 6-fold increase was found in annexin-positive cells after treatment. In terms of mRNA levels, RT-PCR analysis indicated that, although Bax and Caspase-3 were increased, Bcl-2 was decreased after oil treatment. According to our results, S. syriaca essential oil has promising phytochemicals that might be useful in cancer treatment due to their relatively cytotoxic and apoptotic activities in Caco-2 cells.

Veterinary drugs are extensively and legally consumed to treat and prevent disease in chattels but some are also used illegally as growth-stimulating agents. Inappropriate or intensive use of antibiotics can cause allergic reactions and, above all, antibiotic resistance. A multiclass approach for the screening of antimicrobial substances in milk was validated in consonance with Commission Decision 2002/657/EC and to the European guideline for the validation of screening methods for veterinary medicines. This biochip-based approach enables the simultaneous determination of a total of 13 sulphonamide, dapsone and trimethoprim. For monitoring of antibiotic residues, 53 UHT milk samples collected from Tehran, IR Iran were screened applying this technology. The result showed that for all antibiotic residues, the positivity threshold T was much more than the cut-off value Fm. A false positive rate of less than 5% was found for all antibiotics which are satisfactory. All detection capabilities (CCβ) were well below the Maximum Residue Level (MRL) set by the European Commission (100 µg/kg for the sum of all sulphonamides and 50 µg/kg for trimethoprim in milk). The screening results of 53 milk samples showed that 71.7% of samples were compliant and all positive samples were below the MRL set by European Commission. This study showed that the biochip-based technique is valid to identify and quantify antibiotic residues in milk at the studied validation levels. The method was rapid, easy, safe, and able to screen 13 sulphonamide, dapsone and trimethoprim from a single milk sample simultaneously with no sample preparation procedure (or just one-step centrifugation).

The resistance of the P. falciparum strain to some of the antimalarial drugs has been a dominant dilemma facing the treatment of this fetid disease. This necessitates the detection and development of new antimalarial agents targeting the P. falciparum. Azetidine-2-carbonitriles reported for its antimalarial activities, could provide an alternative to the customized antimalarial drugs. Leading to the use of quantitative structure-activity relationship (QSAR) studies, which relates the structures of Azetidine-2-carbonitriles with their activities to generate predictive models. The structures were optimized using density functional theory (DFT) DFT/B3LYP/6-31G* basis set to generate their molecular descriptors, where five predictive models were constructed using the generated descriptors. The models were constructed using the genetic function algorithm component of a material studio, where the model with good statistical parameters, high coefficient of determination (R2) = 0.9465, cross-validated R2 (Q2cv) = 0.8981, Q2 (L4O)cv = 0.9272, and highest external validated R2 (R2pred) = 0.6915 was selected as the best model. These statistical results show the robustness, excellent power of prediction, and validity of the selected model. The descriptor, SpMax2_Bhp (the maximum absolute eigenvalue of Barysz matrix for n = 2 was weighted by polarizability), was revealed to be the most influential in the model due to its highest mean effect. The descriptor played a role in the design of sixteen (16) theoretical derivatives of Azetidine-2-carbonitriles using compound 25 as the design template by increasing polarizability of the compounds through substitution of the various group with electron deactivating groups (F, I, Cl, SO3H, CN, NO2, etc.) at different position of the template. The designed compounds were docked with Plasmodium falciparum dihydroorotate dehydrogenase (Pf-DHODH), giving compound D9 the highest binding energy. The designed compounds were further screened for their drug-likeness, where they all pass Lipinski's RO5. All the compounds show good skin permeability coefficient and have low Gastrointestinal absorption while few compounds D1, D2, D3, D14, and D15 inhibiting the CYP1A2.

Wound healing is a complex process and is influenced by different factors. Aimed to enhance the wound healing procedure, the Moxifloxacin bilayer wafer was designed, optimized and evaluated as an advanced wound healing dressing. The wafers were prepared by the lyophilization and casting method. Optimization was done according to the results of bioadhesion force, swelling index, release rate, T40 and T90 (the time to reach 40% and 90% of release). The optimized wafer was evaluated against in-vitro and in-vivo efficacy using the disc diffusion method and histologic evaluation after application on the wound. The optimized formulation contained HPMC, MC, gelatin and PVP with mounts of 50 mg, 25 mg, 2 mg and 10 mg respectively. The hydrophilic bilayer wafer is adhered to the wound up to the end of wound healing. Application of optimized formulation led to the healing of wound 6 days faster without any sign of infection. The application of this wafer promoted wound healing and epithelium regeneration without any inflammation.

The most common diagnostic method for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR). Upper respiratory tract samples, including nasopharyngeal swab (NPS), oropharyngeal swab (OPS), saliva and lower respiratory tract samples such as sputum, are the most widely used specimens for diagnosis of SARS-CoV-2 using RT-qPCR. This study aimed to compare the diagnostic performance of different samples for Coronavirus disease 2019 (COVID-19) detection. It was found that NPS, the reference respiratory specimen for COVID-19 detection, is more sensitive than OPS. However, the application of NPS has many drawbacks, including challenging sampling process and increased risk of transmission to healthcare workers (HCWs). Saliva samples can be collected less invasively and quickly by HCWs with less contact or by own patients, and they can be considered as an alternative to NPS for COVID-19 detection by RT-qPCR. Additionally, sputum, which demonstrates higher viral load can be applied in patients with productive coughs and negative results from NPS. Commonly, after viral RNA purification from patient samples, which is time-consuming and costly, RT-qPCR is performed to diagnose SARS-CoV-2. Herein, different approaches including physical (heat inactivation) and chemical (proteinase K treatment) methods, used in RNA extraction free- direct RT-qPCR, were reviewed. The results of direct RT-qPCR assays were comparable to the results of standard RT-qPCR, while cost and time were saved. However, optimal protocol to decrease cost and processing time, proper transport medium and detection kit should be determined.

Opioids use has been limited due to tolerance and dependence as major unwanted effects. Previous evidence has shown that targeting endocannabinoid signaling can prevent the development of opioid tolerance and dependence. This study was designed to evaluate the effect of phenylmethylsulfonyl fluoride (PMSF), an inhibitor of fatty acid amide hydrolase (FAAH), on morphine antinociceptive tolerance and physical dependence in mice. The antinociceptive effects of PMSF at the doses 60, 120, and 300 mg/kg were investigated. Results showed that PMSF has a notable antinociceptive effect at doses 120 and 300 mg/kg. The dose of (60 mg/kg, i.p.) PMSF was considered as a sub-antinociceptive dose. Morphine tolerance and dependence were induced by twice-daily injection of morphine (10 mg/kg, s.c.) for 10 consecutive days and the last dose on day 11. Tolerance was assessed by the hot-plate test and dependence by naloxone-precipitated morphine withdrawal signs. In the brain, oxidative stress markers include activities of glutathione peroxidase, catalase, superoxide dismutase, and levels of malondialdehyde and glutathione were determined. A sub-antinociceptive dose (60 mg/kg) of PMSF could reduce tolerance in both acute and chronic methods of administration. However, alleviation of dependence and suppression of oxidative stress markers occurred in the chronic administration of PMSF. In conclusion, it seems that PMSF can suppress morphine tolerance and dependence. However, more studies are needed to clarify its mechanism.

Aberrant histone modifications or promoter region hypermethylation of tumor suppressor genes (TSGs) have been recognized as the important epigenetic molecular mechanism in cancer induction. The potential anticancer activities of histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors (DNMTIs) have been investigated in recent years. The current study was assigned to investigate the effect of trichostatin A (HDACI) in comparison to zebularine (DNMTI) on the intrinsic pro-apoptotic (Bax, Bim, and Bak) and anti-apoptotic (Bcl-2, Mcl-1, and Bcl-xL) genes and extrinsic (DR4, DR5, FAS, FAS-L, and TRAIL genes) pathways, DNA methyltransferase 1, 3a, and 3b, histone deacetylase inhibitors 1, 2, and 3, cell viability, and apoptosis in hepatocellular carcinoma (HCC) SK-Hep 1, colorectal cancer SW620, and pancreatic cancer PaCa-44 cell lines. The SK-Hep 1, SW620, and PaCa-44 cells were cultured and treated with TSA and zebularine. To determine cell apoptosis, cell viability, and the relative gene expression level, flow cytometry assay, MTT assay, and qRT-PCR were done respectively. The result indicated that zebularine and TSA changed the expression level of the Bax, Bak, Bim Bcl-2, Bcl-xL, Mcl-1, DR4, DR5, FAS, FAS-L, TRAIL, DNA methyltransferase 1, 3a, and 3b, histone deacetylase inhibitors 1, 2, and 3 by which induced cell apoptosis and inhibit cell growth in all three cell lines. Concluding, TSA induced its role through both extrinsic and intrinsic apoptotic pathways in three cell lines, whereas, zebularine played its role via both pathways in the SK-Hep 1cell line, it had no significant effect on Bcl-2, Bcl-xL, and Mcl-1 gene expression in SW620 and PaCa-44 cell lines.

Epigenetics is the study of heritable modifications in gene expression and reversible forms of gene regulation. Recent in-vitro works have indicated that epigenetics plays a significant role in many types of human cancers e.g. hepatocellular carcinoma (HCC). Diverse cellular functions are regulated by histone acetylation and deacetylation. Histone deacetylases (HDACs) and histone acetylases (HATs) are enzymes involved in chromatin remodeling histone deacetylation and acetylation respectively. Aberrant protein acetylation, particularly histone deacetylation, has been reported in a broad range of human cancer types. Epigenetic modification by inhibiting  HDAC activity is an emerging approach in cancer treatment. HDACIs play their apoptotic roles through multiple mechanisms such as extrinsic/cytoplasmic and intrinsic/mitochondrial molecular mechanisms. Here, we summarize the major classes of HDACs and epigenetic compounds, HDACIs, and also their molecular mechanisms in HCC including intrinsic and extrinsic apoptotic pathways. An online search of different sources including PubMed, ISI, and Scopus was achieved to find suitable data on mechanisms and pathways of HDACs and HDACIs in HCC. The result demonstrated that the dysregulation of HDACs because of histone deacetylation induces HCC. The histone deacetylation can be reversed by HDACIs resulting in apoptosis induction. In conclusion, because histone deacetylation is a potentially reversible change, epigenetic histone modification represents new opportunities for cancer management by reactivation of gene silencing. The inhibition of HDACs by GDACIs can effectively induce apoptosis and suppress cancer cell proliferation. These compounds can engage both intrinsic and extrinsic apoptotic pathways.

Low-temperature plasma (LTP) has demonstrated great potential in biomedicine, especially in cancer therapy in-vivo and in-vitro. Plasma activated water (PAW) as an indirect plasma therapy is a significant source of reactive oxygen and nitrogen species (RONS) which play an important role in apoptosis induction in cancer cells. In this study, Helium (He) plasma jet operating in 0.75 W and 20 kHz as dissipated power and frequency, respectively, is used as the cold plasma source. The electrical, thermal, and spectroscopic properties of (He) plasma jet and pH as well as the conductivity and temperature of PAW samples, are investigated. The concentration of hydrogen peroxide (H2O2), nitrite (NO2 -) and nitrate (NO- 3), which are produced in water as long-lived anticancer RONS, was measured 471.6, 7.9 and 93.5 μM, respectively after 6 min of plasma treatment. Alamar Blue and flow cytometry assays were employed to investigate the B16F10 cancer metabolic activity and apoptosis. These data support that cold atmospheric plasma (CAP) can produce a certain concentration of anti-cancer agents in water and induce apoptosis in melanoma cancer cells due to RONSs via activating the caspase 3 pathway.

We synthesized twelve hybrids, S-allyl Cysteine methyl, ethyl and propyl ester-based non-steroidal anti-inflammatory drugs and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of all compounds was evaluated against SW480 human colon adenocarcinoma cells and the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 10b-c, 11b and 12b displayed the best anticancer activity with IC50 values between 0.131-0.183 mM and selectivity indices higher than 1 after 48 h of treatment. Selectivity indices were comparable to those reported for the reference drug, 5-fluorouracil (SI > 1). The SAR analysis showed that compounds with two carbon atom alkylic chains displayed the best activity (10b, 11b and 12b). Modeling studies including drug-likeness, bioactivity score and ADME/tox studies using online tools like molinspiration and Osiris suggested that these designed hybrids have a good pharmacological profile and can be considered as promising scaffolds for further studies in the search for new therapeutic alternatives to treat colorectal cancer.

Due to the lack of suitable therapeutic approaches to cartilage defect, the objective of this study was to determine the effect of Transforming growth factor-β3 (TGF-β3), avocado/soybean (ASU) and Kartogenin (KGN) on chondrogenic differentiation in human adipose-derived stem cells (hADSCs) on fibrin scaffold. hADSCs seeded in fibrin scaffold and cultured in chondrogenic media. These cells were divided into 4 groups (control, TGF-β3, ASU and KGN). Cell viability was estimated by MTT assay. Differentiated cells were evaluated by histological and immunohistochemical (IHC) techniques. Expression genes [sex determining region Y-box 9 (SOX9), Aggrecan (AGG), type II collagen (Coll II) and type X collagen (Coll X)] were assessed by real-time PCR. For a study on an animal model, differentiated cells in fibrin scaffolds were subcutaneously transplanted in rats. Histological and immunohistochemistry were done in the animal model. The results of the real-time PCR indicated that SOX9, AGG and Col II genes expression in TGF-β3, KGN and ASU groups were significantly higher (p < 0.01) compared to the control group, Col X gene expression only in the TGF-β3 group was significantly higher (p < 0.01) compared to the control group. The glycosaminoglycan (GAG) deposition was higher in TGF-β3, KGN and ASU groups compared to the control group. The immunohistological analysis showed the distribution of collagen type X in the extracellular matrix in the fibrin scaffold TGF-β3 group was significantly higher in control, KGN and ASU groups, and (p < 0.001). ASU, particularly KGN, was suitable for successful chondrogenic differentiation of hADSCs and a suppressor of the consequent hypertrophy.

In this study, we focused on quetiapine fumarate (QTF), a class II BCS drug. QTF is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorders. Our objective was to develop a new QTF-loaded self-emulsifying drug delivery system (SEDDS) to improve the dissolution and absorption of the drug. An experimental design approach was used to develop and optimize QTF-loaded SEDDS. The optimized formulation was characterized for droplets size, zeta potential, PDI, and stability. It was then evaluated using an in-vitro combined test for dissolution and Everted gut sac technique. Mathematical modeling and Transmission electron microscopy (TEM) were used to elucidate the mechanism of release. The optimal formulation was type IIIB SEDDS, constituted of 9.1% of oleic acid, 51.6% of Tween®20, and 39.3% of Transcutol® P. It showed a droplets size of 144.8 ± 4.9nm with an acceptable PDI and zeta potential.For in-vitro evaluation tests, we noticed an enhancement of the dissolution rate of the optimal QTF-loaded SEDDS compared to the free drug (98.82 ± 1.24% for SEDDS after 30 min compared to 85.65 ± 2.5% for the pure drug). The release of QTF fitted with the Hopfenberg model indicating the drug was released by water diffusion and erosion mechanism. This result was confirmed by TEM images which showed a smaller droplet size after release. We also found an amelioration of the permeability of QTF of 1.69-fold from SEDDS compared to the free drug.Hence, the SEDDS formulation represented a new way to improve the dissolution and absorption of QTF.

The recent prevalence of novel “coronavirus disease 2019” has expanded quickly globally, causing a universal pandemic. Herein, an effort was constructed to design a potent drug to inhibit the main protease of SARS-Cov-2 (3CLp) by means of structure-based drug design. A large library of the compounds was used for virtual screening. After molecular docking and ADME studies, we selected a compound with a better binding affinity to the 3CLp active site and acceptable ADME properties compared to the selected positive control drug. Molecular dynamic (MD) simulation (200 ns) and Molecular Mechanics–Poisson Boltzmann Surface Area (MM-PBSA) were used for further analysis. MD simulation outcomes have proved that the 3CLp-ZINC31157475complex possesses a considerable value of dynamic properties such as flexibility, stability, compactness, and binding energy. Our MM-PBSA computation illustrates that ZINC31157475is more potent (-88.03 kcal mol-1) than nelfinavir (-19.54 kcal mol-1) against COVID-19 3CLp. Further, we have determined that the main residues of the 3CLp interact with ligands from per-residue binding energy. In conclusion, we suggest that ZINC31157475can potentially treat COVID-19 by inhibition of the 3CLp. However, in-vitro and in-vivo study is essential for approval of this suggestion.

Timely repair of damaged skin is very important to maintain the integrity and homeostasis of skin, but the wound healing process is compromised in diabetic patients due to several extrinsic and intrinsic factors thus lead to leg amputation and death eventually. Sirtuins, a family of seven conserved proteins are known to be associated with pathophysiological processes of the skin. The most important among them are sirt1and sirt3 involved in cell regeneration and cell survival. Naphthoquinone derivatives have a wide range of therapeutic properties, but the potential diabetic wound healing activity of lapachol has not been identified yet. The present study thus aimed to investigate the wound healing effects of lapachol in a diabetic mouse model. Diabetic wounded mice were divided into 3 groups; vehicle, lapachol 0.05%, and lapachol 0.1%. Skin samples collected from diabetic wounded mice on different time points after treatment for 10 consecutive days were subjected to downstream analysis by western blot, ELISA and histology. Lapachol treatment was found to enhance the expression of sirt1/sirt3 and other proteins involved in cell migration and blood vessel formation. The tissue development rate was increased by lapachol treatment with better collagen deposition. Interestingly, lapachol treatment also gave rise to a high concentration of growth factors resulting in speedy and timely recovery of injured skin. In summary, our findings suggest that lapachol promotes efficient wound healing in a diabetic mouse model by increasing the expression of sirt1 and sirt3 and other proteins related to wound repair and skin regeneration including α-PAK, RAC1/CDC42, VEGF and growth factors viz PDGF and VEGF. This research work finds a novel potential activator of sirtuins in the form of lapachol and depicts the role of activated sirtuins in diabetic wound healing.

Drug-induced liver injury (DILI) is one of the most serious adverse effects of anti-tuberculosis (TB) drugs. A suggested mechanism of this adverse effect is mitochondrial dysfunction (MDF). The purpose of this study was an evaluation of the possible preventive effects of the combination of acetyl-L-carnitine (ALCAR), alpha-lipoic acid (ALA), and coenzyme Q10 (CoQ10), as mitochondrial nutrients (MNs), against anti-TB DILI.In this clinical trial, patients who met the inclusion criteria were randomly assigned to either experimental (n = 44) or placebo (n = 43) groups. The experimental group received capsules containing CoQ10 (200 mg) + ALA (250 mg) + ALCAR (250 mg) orally twice daily for two weeks, and the placebo group received oral placebo capsules with the same interval and duration. The mean serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBil) at the end of the first and second weeks as well as the incidence of DILI during the intervention were recorded and compared between the two groups.At the end of the study, the mean serum levels of AST and ALT in the experimental group were significantly lower than the placebo group (36.27 ± 36.43 vs. 86.02 ± 97.23 and 28.41 ± 27.41 vs. 78.80 ± 118.28, respectively, p = 0.003 for both).Also, the incidence of anti-TB DILI was significantly lower in the experimental group than the placebo group (6.8% vs. 25.6%, p = 0.017). In conclusion, using the combination of ALCAR, ALA, and CoQ10 may provide an effective strategy in preventing anti-TB DILI.

Juniperus speciesgrowing in Turkey are used for various medicinal purposes in traditional folk medicine. We aimed to evaluate in-vitro antidiabetic (α-glucosidase and α-amylase inhibition assays), antiobesity (pancreatic lipase inhibition assay), and antioxidant (ABTS and DPPH radical scavenging activities, ferric reducing activity, metal chelating activity, and phosphomolybdenum assay) activities of the extracts obtained from branches, leaves, and fruits of Juniperus macrocarpa and Juniperus excelsa. The branch (IC50 =  67.1 ± 1.7 µg/mL) and leaf ethyl acetate extracts (IC50 =  83.4 ± 0.8 µg/mL) of J. macrocarpa exhibited the strongest activity on the α-glucosidase enzyme. Besides that, J. excelsa leaf methanol extract exerted remarkable α-amylase inhibitory activity (IC50 = 950.1 ± 3.5 µg/mL). Only J. macrocarpa branch and J. excelsa leaf ethyl acetate extract slightly inhibited pancreatic lipase enzyme with 2963.3 ± 736.4 and 2343 ± 557.8 µg/mL IC50 values, respectively. The RP-HPLC-DAD analysis results demonstrated that the more active J. macrocarpa extracts are richer in agathisflavone, amentoflavone, and umbelliferone than J. excelsa extracts. With this study, it is concluded that J. macrocarpa branch and leaf ethyl acetate extracts may be a new source of α-glucosidase enzyme inhibitory activity and agathisflavone, amentoflavone can be used in the standardization of the extracts.

The functionalized 2-pyridone-3-carboxylic acids were synthesized starting from 3-formylchromone. Meanwhile, a decarboxylation reaction of 2-pyridone-3-carboxylic acid was performed by potassium carbonate in toluene. All compounds were evaluated against two Gram-negative bacteria (Escherichia coli (E. coli), Acinetobacter baumannii (A. baumannii)) and two Gram-positive (Staphylococcus aureus (S. aureus)) and fungus (Candida albicans (C. albicans)) using serial broth dilution method. The antimicrobial screening revealed that S. aureus is the highest sensitive microorganism towards the synthesized compounds. Among all analogs, derivatives, 4p and 5c showed excellent activities in comparison with the other compounds against S. aureus. Molecular docking showed that the most active anti S. aureus are compounds 4p and 5c exhibiting primary interaction as with fluoroquinolones by cross-linking over DNA gyrase active site via metal ion bridge and H-bonding interaction with Ser84 and Glu88 from GyrA subunit along with Arg458 and Asp437 located at GyrB subunit. In addition, based on the molecular dynamic simulation as like the standard fluoroquinolones, the mentioned compounds were stabilized for significant amount of simulation time over DNA gyrase which potentiate the importance of the mentioned residues in the DNA gate region of DNA gyrase.

Oliveria decumbens Vent. has been used by indigenous people of southwest Iran for treating peptic ulcers and gastrointestinal infections. This study aimed to investigate the antibacterial activity of Oliveria decumbens extract and fractions and to analyze the bioactive components of the fractions. Total plant extract and different fractions of Oliveria decumbens Vent. were prepared. Antibacterial activities were evaluated against the clinical strain of Helicobacter pylori and standard strains of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa using agar dilution and disc diffusion methods. Phytochemical analysis of the fractions was performed using silica gel chromatography and 1D and 2D NMR spectroscopy. Moreover, the urease inhibitory effects of the isolated compounds were assessed in-vitro and in-silico. Three novel kaempferol derivatives and two thymol derivatives were isolated from Oliveria decumbens aerial parts, and the structures were determined by comparison with published data. The n-hexane fraction was found to exert the most significant anti-H. pylori activitywith the minimum inhibitory concentration of 50 µg/mL. All fractions demonstrated antibacterial activity toward S. aureus. In-vitro urease inhibition assay showed that stigmasterol, tiliroside, and carvacrol were found to be the most potent enzyme inhibitors in the isolated compounds. Molecular interactions of the compounds with the active site of urease were supported by the molecular docking analysis. Novel bioactive compounds in Oliveria decumbens were described in this study. The antibacterial effects suggested the potential use of the compounds in pharmaceutical formulations inconsistent with the traditional use of the plant in the treatment of gastrointestinal infections.

In the present study, simultaneous voltammetric determination of noscapine (NOS) and lorazepam (LOR) was studied for the first time. A carbon paste electrode modified with multi-walled carbon nanotubes (MWCNTs) and natural deep eutectic solvent (NANADES) (MWCNTs/NADES/CPE) was used for this purpose. Electrochemical impedance spectroscopy (EIS) was applied for the investigation of the electron transfer rate of [Fe(CN)6]3-/4- as a redox couple probe on the surface of the MWCNTs/NADES/CPE. The modified electrode preserved and combined the properties of the individual modifiers synergistically. A significant enhancement in the peak current responses of NOS and LOR was observed on the modified electrode surface compared to the bare electrode. Under the optimal conditions, the peak current of differential pulse voltammograms was linearly dependent on analyte concentration in the range of 3-1700 µM for NOS and 1-2220 µM for LOR. The limit of detection (LOD) for NOS and LOR was 1.90 µM and 0.69 µM, respectively. Finally, this strategy was also employed for the determination of NOS and LOR in pharmaceutical samples.

Methotrexate (MTX) is one of the most effective therapeutics to treat different types of solid tumors; however, it suffers low permeability limiting its bioavailability and cellular uptake. To tackle this, we aim to design and fabricate different types of cell-penetrating peptides (CPPs) to improve the intracellular uptake of MTX without causing any immunogenic response. CPPs were synthesized by the solid-phase peptide synthesis method. Peptide-MTX conjugates were prepared via covalent binding of peptide and drug molecule. CPPs and peptide-E8 nanoparticles were characterized using zeta-sizer and scanning electron microscopy. Cytotoxicity of CPPs and peptide-MTX conjugates was evaluated by MTT assay. An enzyme-linked immunosorbent assay was employed to assess the IL-6 and TNF-α cytokine release profile. Amongst all sequences, W4R4-MTX possessed the highest loading efficiency (97%) and drug to peptide percentage (24.02%). The lowest loading efficiency (36%) and drug to peptide percentage (8.76%) were seen for NGRWK-MTX conjugates. The NGRWR peptide and NGRWR-E8 nanoparticles had acceptable size (~100 nm) with spherical and rod-like structures, respectively. The selected CPPs and peptide-MTX conjugates did not show any cytotoxicity or immunogenicity. The fabricated peptides are represented as promising carriers to improve the intracellular delivery of MTX to cancer cells with low immunogenic and cytotoxic effects on normal cells.

Cancer is the second cause of death in the world and the discovery of novel anticancer agents is of vital importance to provide better therapeutic options for cancer patients. In this study, a new series of 12 arylidene hydrazone phenanthrotriazine derivatives were designed, synthesized, and tested in-vitro for antiproliferative activity against three cancer cell lines including colorectal cancer (HT-29), breast cancer (MCF-7) and leukemia (MOLT-4) cells and also against Vero normal cells. The effect of derivatives on cell cycle and apoptosis induction were studied by flow cytometric propidium iodide/RNase assay and Hoechst 33258 staining, respectively, while docking analysis was used to investigate the interactions of synthesized derivatives with the c-Met receptor kinase domain. Some compounds showed considerable antiproliferative activity against tested cancer cells. The most potent derivative was 9k bearing pyrrole moiety with IC50 values of 14.3, 4.7 and 1.7 µM against HT-29, MCF-7 and MOLT-4 cells, respectively, while it showed negligible activity against Vero normal cells (IC50: 95.4 µM). Derivatives bearing 2-nitrophenyl (9g), 4-cyanophenyl (9j), pyrrole (9k), and thiophene (9l) moieties induced G0/G1 cell cycle arrest and also apoptosis at higher doses in MCF-7 cells. Docking study showed that the phenanthrotriazine backbone form H-bond interactions with Asn1209, while phenyl moieties of the pendants generate different hydrophobic interactions with the Asp1164 and Asp1231 residues of c-Met. In conclusion, phenanthrene 1,2,4-triazines, especially the ones with less influence on normal cells, may constitute promising compounds for the discovery of antiproliferative agents with potential c-Met inhibitory capacity.

Metronidazole (MTZ) can decrease the levels of several cytokines. This research aimed at the investigation of the anti-inflammatory impact of MTZ in COVID-19. A randomized, single-blind clinical trial for comparing the anti-inflammatory effect of MTZ in two eligible groups of adult patients with lower respiratory tract involvement due to Covid-19 treated with a standard national method with or without MTZ was performed. Inflammatory markers were measured as the primary outcome in two groups. Oxygen saturation, length of hospital stays, and mortality of patients were evaluated as secondary outcomes. Among 44 patients with lower respiratory tract due to Covid-19, 20(45.5%) were randomly allocated in group A with the current standard treatment plus the MTZ tablet for 7 days orally and 24 (54.5%) in group B with the current standard treatment. The mean of ESR in group A was statistically significantly lower than that of group B on the seventh day (A: 38.25 ± 18.75 vs. B: 47.67 ± 26.41, p = 0.02). Moreover, the mean of IL6 diminished significantly in both A (p = 0.01) and B (p = 0.01) groups on the seventh day compared to the first day. The decrease of TNF was not significant in any of the groups A (p = 0.3) and B (p = 0.4) from the 7th day to the first day. No significant difference was not found between group A and group B groups on the CRP level (p = 0.1). Findings of this study showed the anti-inflammatory impact of MTZ in the patient with lower respiratory inflammation due to COVID-19.

Since 2018, regulation and control of genotoxic nitrosamine impurities levels have been a mandatory quality and safety characteristic for various drugs. The main issue of nitrosamine determination in drugs is a low sensitivity of the existing methods and a continuously extending list of controlled compounds. The reason is the low safe daily dose of these impurities and chromophores' absence within their structure. Development and validation of a method for nitrosamine impurities (regulated by the regulatory authorities) determination in Valsartan, Losartan, and Irbesartan using high-performance liquid chromatography with mass spectrometry detection. An Agilent Infinity II chromatographic system with a mass spectrometric detector (MSD 6460 Triple Quad) and atmospheric pressure chemical ionization was used in this study. During the development of a method, the optimal conditions for chromatographic separation (composition of mobile phases, gradient parameters) were selected, as well as the parameters of mass spectrometric detection were optimized. The usage of chemical ionization made it possible to achieve the method's maximum sensitivity concerning the studied nitrosamines, and the optimized parameters of mass spectrometric detection made it possible to get rid of the matrix effect. The absence of additional stages of purification and concentration can significantly reduce the total time of the analysis, which is a significant advantage of nitrosamine's advanced determination method. The resulting method was validated for specificity, linearity, LOQ, LOD, accuracy, and precision. Resulting method met all acceptance criteria and can be used for routine quality control of Valsartan, Losartan, and Irbesartan pharmaceutical substances.

COVID-19 pandemic has created a global health challenge. Many pharmaceuticals have been repurposed as potential treatments, though many have not been promising. Due to the inflammatory and destructive effects of the virus on alveolar cells, the effect of exogenous surfactant was assessed as a potential treatment of lung dysfunction in COVID-19 patients. In this pilot study of the clinical trial, 49 patients aged 35-80 years with COVID-19 admitted in ICU entered the study (22 patients intubated and 23 had face masks; 4 patients in the control arm). The treatment arm patients received two consecutive doses of surfactant. P/F ratio (based on serial blood gas analyses before and 12 hours after 2 doses of surfactant) and also, clinical outcomes were assessed.in COVID-19 adult patients, surfactant significantly improved pulmonary P/F ratio both in intubated and face mask COVID-19 patients (increasing from 119.2 ± 51.7 to 179.4 ± 115.5). The rate of extubation was much better than similar country-wide studies. Surfactant significantly alleviates the respiratory status in moderate to severe COVID-19 ARDS with two consecutive 100 mg doses of surfactant (with 6 hours' interval) though previous studies have been controversial, regarding the effect of surfactant in general forms of ARDS. Higher doses might have better effects, mandating more trials.

< p>Computer-aided drug design provides broad structural modifications to evolving bioactive molecules without an immediate requirement to observe synthetic restraints or tedious protocols. Subsequently, the most promising guidelines with regard to synthetic and biological resources may be focused on upcoming steps. Molecular docking is common in-silico drug design techniques since it predicts ligand-receptor interaction modes and associated binding affinities. Current docking simulations suffer serious constraints in estimating accurate ligand-receptor binding affinities despite several advantages and historical results. Response surface method (RSM) is an efficient statistical approach for modeling and optimization of various pharmaceutical systems. With the aim of unveiling the full potential of RSM in optimizing molecular docking simulations, this study particularly focused on binding affinity prediction of citalopram-serotonin transporter (SERT) and donepezil-acetyl cholinesterase (AChE) complexes. For this purpose, Box-Behnken design of experiments (DOE) was used to develop a trial matrix for simultaneous variations of AutoDock4.2 driven binding affinity data with selected factor levels. Responses of all docking trials were considered as estimated protein inhibition constants with regard to validated data for each drug. The output matrix was subjected to statistical analysis and constructing polynomial quadratic models. Numerical optimization steps to attain ideal docking accuracies revealed that more accurate results might be envisaged through the best combination of factor levels and considering factor interactions. Results of the current study indicated that the application of RSM in molecular docking simulations might lead to optimized docking protocols with more stable estimates of ligand-target interactions and hence better correlation of in-silico in-vitro data.

The present study aimed to estimate the potential and the molecular mechanism of the hydro-ethanolic extract of O.floribundum against acetaminophen (AC) induced hepatotoxicity. Four groups of female Wistar rats (n=6) was formed to study the hepatoprotective effect of O.floribundum extract against acetaminophen overdose (2 g/kg): Groups N and AC received orally tap water for 03 days and Groups O. floribundum + AC and N+O.floribundum: received orally O. floribundum extract (400 mg/kg). After 1hour (h) of the last dose administered, the paracetamol solution (2 g/kg) is administered orally for group AC and O. floribundum + AC. The hydroethanolic extract of O. floribundum shows strong antioxidant activity "in-vitro". After 24 h, asingle dose of acetaminophen increased significantly serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the activity of alkaline phosphatase (ALP) significantly and decreased total protein and albumin levels compared to the normal group. These alterations are confirmed by histological observations with inflammation markers (congestion, inflammatory cells infiltration). These observed effects are mainly due to the over-expression of the CYP2E1 and NF_κB genes marked in this study by quantitative RT-PCR. Also, acetaminophen overdose leads to activation of the mitochondrial permeability transition (MPT). leading to hepatocyte necrosis. Pretreatment with O.floribundum before acetaminophen administration removes all previously observed biochemical, histological. and mitochondrial manifestations. These results suggest that O.floribundum has a potent antioxidant power and an interesting hepatoprotective activity against acetaminophen toxicity partly due to the inhibition of CYP2E1 and NF_κB genes expression.

Improving the bioavailability of a drug at the ocular surface presents a profound challenge. Due to ocular physiological barriers, conventional eye drops exhibit poor bioavailability of drugs. Sustained-release nanoparticles may improve the residence time and hence increase absorption of the drug from the corneal surface. The current study focuses on the development of a nanoparticle-based system for the ophthalmic sustained delivery of moxifloxacin, to enhance ocular retention and bioavailability of the drug. PLGA was used as the matrix-forming polymer inthe nanoparticle formulation. Nanoparticles were manufactured using a double emulsion (w/o/w) solvent evaporation technique. The formulation was optimized based on physicochemical properties, including size, polydispersity index, and stability. Nanoparticles were also evaluated for in-vitro drug release and pharmacokinetic evaluation in a rabbit model. The optimized formulation exhibited a relatively high initial release rate for six hours followed by sustained release of a drug via diffusion. The in-vivo ocular tolerance studies confirmed that moxifloxacin-loaded PLGA nanoparticles were non-irritating to the eye. The pharmacokinetic studies revealed that the nanoparticles provided a high Cmax, AUC, MRT, and low clearance rate when compared to commercial eye drops. It can be concluded that such PLGA nanoparticles offer the potential for improved bioavailability of moxifloxacin HCl.

Recently, it has been found that abnormal activation of inflammasomes, the intracellular multiprotein complexes, plays an important role in the pathogenesis and the development of inflammatory diseases. To determine whether the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is involved in chronic inflammatory condition reported in glomerulonephritic- hemodialysis (HD) patients, we investigated the mRNA levels of NLRP3, CASP-1, ASC, IL-1β, IL-18, NLRC4, and P2X7 in human peripheral blood mononuclear cells (PBMCs) collected from 28 glomerulonephritic-HD patients. To confirm the mRNA quantification results, we investigated the IL-1ß content and Caspase 1 activity in serum and PBMC lysates, respectively. Compared with PBMCs derived from healthy subjects, genes encoding proinflammatory cytokines such as IL-1β and IL-18 as well as NLRP3, ASC, CASP-1 were markedly overexpressed in those derived from patients. Moreover, there was no significant difference between the expression level of P2X 7 mRNA in PBMCs isolated from glomerulonephritis-HD patients and controls. The serum level of active IL1-β and cell lysate CASP-1 activity were up-regulated in patients compared to controls. We also revealed that PBMCs isolated from glomerulonephritis-HD patients had elevated mRNA levels of NLRC4 compared to controls, suggesting the priming of NLRC4 inflammasome. These results revealed that the NLRP3-ASC-caspase-1 axis might have a role in increased inflammation severity reported in glomerulonephritic patients undergoing hemodialysis. These findings provide new insights into molecular mechanisms underlying chronic inflammation in HD- glomerulonephritic patients. Additionally, the NLRP3 inflammasome pathway can be attractive as a potential therapeutic target for complication avoidance in HD- glomerulonephritic patients.

Three novel Cr(III) complexes, [Cr(dafone)2(H2O)2](NO3)3 (1), [Cr(opd) (dafone)2](NO3)3 (2) and [Cr (phen-dione) (dafone) (H2O)2].(NO3)3 (3) were synthesized and characterized by different techniques. Fluorescence spectroscopy, gel electrophoresis, viscosity measurement, and circular dichroism (CD) were applied to explore the interaction of Cr complexes with FS-DNA. The binding constant (Kb) was obtained from UV–Vis measurements. The obtained results exhibited the effective binding of target complexes to DNA double-strand. The fluorescence data appraised both binding and thermodynamic constants of complexes-DNA interactions. The measured thermodynamic factors (∆S˚, ∆H˚, ∆G˚) revealed that hydrogen bonding and van der Waals forces for DNA- Cr(III) complexes bear the most important roles. As well, the Stern–Volmer quenching constants (Ksv) and the binding constants (Kb) of synthesized compounds and DNA were calculated. The results of thermodynamic parameters showed that the binding of synthesized Cr(III) compounds to DNA was driven mainly through hydrogen bonds and van der Waals interactions. Viscosity measurement results showed that increasing the concentration of synthesized compounds, did not make any major changes in specific viscosity of FS-DNA. The data of viscosity and circular dichroism (CD) support the groove binding mode.

The anticancer and immunomodulatory effects of medicinal plants from Golestan province, as a promising source of cancer therapy against gastrointestinal cancer cell lines, were investigated in this study. The ethanolic root/aerial part extracts of 9 medicinal plants were screened for their cytotoxicity against normal mouse fibroblast cells (L-929) and three human cancer cell lines including gastric adenocarcinoma (AGS), colorectal adenocarcinoma (HT-29), and esophagus adenocarcinoma (KYSE-30) by performing MTT assay to determine the IC50 of the extracts. The in vitro antioxidant activity, total phenolic (TPC), and total flavonoid content (TFC) of extracts was evaluated. Flow cytometry and Real-Time PCR were used for apoptosis assay and evaluation of expression of some genes involved in cell signaling; TLR-4, AKT, ERK1/2, and NFκB. Out of the 9 plant extracts screened, Arctiumlappa root (ALR), showed the most potent cytotoxicity against AGS, KYSE-30, and HT-29 cells with IC50 values of 10, 200, and 2030 µg/mL, respectively. In addition, ALR exerts high TPC (215.8 ± 0.3 mg GAE/g), TFC (69.03 ± 0.7 mg QUE/g) and high radical scavenging activity with IC50 (1250 ‎±‎ 0.1 µg/mL) in DPPH method. Also, ALR stimulates TLR-4 signaling, increased apoptosis, and decreased cancer cell attachment to the surface compared to the untreated cells. This plant, with a strong cytotoxic effect on cancer cells as well as increased apoptosis and its effect on molecules involved in TLR4 signaling as the immunomodulatory effect can be a suitable candidate for in-vivo studies in the future for cancer therapy.

The aim of this study was to compare the insulin glargine and detemir effects on hormons affecting appetite and metabolic control of patients with type 1 diabetes. This single-blind randomized clinical trial was conducted on patients aged 2 to 18 years with type 1 diabetes who were referred to the endocrinology department of Ali-Asghar Children Hospital in Tehran, from April to September 2019. Patients were randomly allocated to receive insulin Glargine or insulin Detemir. Before starting treatment, blood samples were obtained for routine biochemical tests and factors affecting appetite, including Leptin, Ghrelin, Aguti-Related Peptide (AGRP), and Peptide-YY3-36 (PYY 3-36). Patients were evaluated monthly and insulin dose was adjusted based on target glucose and carbohydrate counting. At the end of three months, the anthropometric values , HbA1C and factors that influence appetite were measured again in both groups, and the results were compared. A total of 40 children with a new onset of type 1 diabetes under 18 years who were hospitalized in Ali Asghar Children Hospital were randomly assigned into two groups as Glargine (n = 20) and Detemir (n = 20). The mean age of patients in the Glargine group was 11.07  ±4.18 years and in the Detemir group was 8.06 ± 3.56. In Glargine group HbA1C, Cholesterol, LDL, AGRP significantly decreased and leptin increased after treatment., while the change of BMI Z-score was not significant. There was a significant decrease of  HbA1C in the Detemir group after treatment but there was no significant change of other variables.  There was no significant difference for all the variables between two groups after treatment.  There was no significant difference for BMI, metabolic control and appetite hormones between Glargine and Detemir groups. BMI-z score did not change in Glargine group while leptin increased and AGRP decreased after treatment. HbA1C decreased significantly after treatment in both groups.