Pharmaceutical Sciences
Volume:29 Issue: 2, Apr 2023

For years, the health benefits of coumestrol (CMT) have been investigated by researchers around the world. Anti-oxidative properties of the phytoestrogen which can be extracted from several plant tissues, have already been reported as well as the cancer chemopreventive capabilities. Recently, psychiatric and neurological effects of this natural compound have become of interest to researchers so that strong evidence would support the idea that CMT can exert significant effects on the central nervous system. Pharmacologically, this phytoestrogen would act as a selective estrogen receptor modulator with several-fold more affinity to β sub-types of the receptors (ERβ); although other mechanisms of action may be involved. The aim of this review was to gather the recent reports regarding the most important pharmacological benefits of CMT focusing on the psychiatric and neurological ones. Furthermore, the mechanisms of action underlying the pharmacological effects were tried to be clarified more. For this purpose, some keywords such as “Coumestrol”, “Pharmacological Effects”, “Neurological”, ”Psychiatric” and “Neuropsychiatric” were searched in popular scientific databases such as Google scholar, Scopus and Pubmed. Then the delegated documentations were brought together, categorized and discussed on this basis. Reviewing the gathered information showed that, apart from the effects on reproduction and the related organs which are mainly conducted through estrogen receptors, CMT has reported to improve various disorders all over the body. Particularly, regarding the neurological and psychiatric systems, the advantages in cerebral hypoxia-ischemia, the Alzheimer’s disease, anxiety, depression and cognitive impairments would be the most important ones. Here, other receptors that have shown interactions with CMT (beside estrogen receptors which are the main target), were also reviewed among which insulin receptors, farnesoid X receptors, pregnane X receptors, and constitutive androstane receptors can be mentioned while only the last two seem to be involved in forming the neurological and psychiatric effects.

Alpha-amylase is one of the most widely used enzymes in the starch industry. However, industrial application of soluble alpha-amylase is hampered by changes in pH and temperature (adverse effects on enzyme stability) and activity loss, leading to higher costs. Immobilization of alpha-amylase is an efficient strategy to reduce the enzyme losing and subsequently reduces costs in this regard. Alpha-amylases are immobilized by adsorption, entrapment, covalent attachment, and cross-linking. A barrier in alpha-amylase immobilization is the large size of its substrate, namely amylose and amylopectin. Most of these immobilization methods decrease the affinity of the enzyme for its substrate as well as the maximum rate of reaction (Vmax). This review aims to study different aspects of alpha-amylase including enzyme activity, applications, structure, starch, immobilization methods, and immobilization’s obstacles to improve alpha-amylase efficiency in the industry and also lowering the costs related to providing this enzyme.

A new chapter in the pharmaceutical industry has been created by 3D printing, particularly in the manufacturing of solid preparations. This technology can support the modification of medicine in terms of drug dosage. Furthermore, it is achieved by adjusting the volume of tablets while being designed using the software to meet the required dose. The research aims to review several polymers used in 3D printing through the fused deposition modeling (FDM) technique. The polymers in filament fabrication for 3D printed tablets should be thermoplastic and have the appropriate mechanical properties for further processing steps. This review focuses on studying the characteristics of polymers such as polylactic acid, polyvinyl alcohol, polycaprolactone, polyvinyl pyrrolidone, polyethylene oxide, ethylene vinyl acetate, ethyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose. Additionally, it discusses the effect of these polymers on the drug release profile from the 3D printed tablets.

 Cholestasis is a multifaceted disease that influences not only the function of the liver but also affects many other organs. In this context, cholestasis-induced lung injury is a significant clinical complication. Unfortunately, there is no precise therapeutic option against cholestasis-associated lung injury. It has been revealed that oxidative stress and inflammatory response play a role in cholestasis-induced pulmonary damage. Sildenafil is a phosphodiesterase enzyme inhibitor used in the management of erectile dysfunction. Meanwhile, several experiments revealed the effects of sildenafil on oxidative stress and inflammation. This study aimed to evaluate the effect of sildenafil on cholestasis-induced oxidative stress and inflammation in cholestasis-induced lung injury.

 Rats underwent bile duct ligation (BDL) to induce cholestasis. Bronchoalveolar lavage fluid (BALF) levels of inflammatory cells, cytokine, and immunoglobulin were monitored at (3, 7, and 14 days after BDL surgery). Moreover, lung tissue histopathological alterations and biomarkers of oxidative stress were evaluated.

 A significant increase in BALF inflammatory cells, TNF-α, and immunoglobulin G (IgG) was evident in BDL animals. Moreover, the infiltration of inflammatory cells, vascular congestion, and hemorrhage were detected in the lung of BDL rats. Increased markers of oxidative stress were also evident in the lung of BDL animals. Sildenafil (10 and 20 mg/kg) significantly blunted inflammatory response, oxidative stress, and histopathological alterations in the lung of cholestatic animals.

 The effects of sildenafil on inflammatory response and oxidative stress biomarkers seems to play a crucial role in its protective properties in the lung of cholestatic animals.

 Sepsis promotes severe physiologic alterations in patients, and it has been reported to induce profound changes in the gut microbial composition. The decrease of ‘health‑benefiting’ microbes and the increase in dysbiosis in critically ill patients are thought to induce or aggravate sepsis. In this study, we aimed to explore the effect of a probiotic preparation, Lactocare®, on gut microbiota in critically ill septic patients admitted to the intensive care unit (ICU).

 Forty critically ill patients diagnosed with sepsis were assessed in this pilot randomized controlled trial. Patients were randomized into two groups: Lactocare and control groups. Patients in the Lactocare group received two capsules of Lactocare® for 10 days. Fecal samples were taken from all patients on days 1 and 10 for determining the gut microbial pattern. The primary outcome was gut microbial flora, and secondary outcomes were intensive care unit (ICU) length of stay and mortality.

 Intragroup changes showed that all microbial flora considerably changed during the study period; the number of microbial flora significantly decreased in the control group and increased in the Lactocare group. Patients in the Lactocare group had a significantly lower incidence of diarrhea and infection with multidrug-resistant organisms. There was no difference in ICU length of stay in the Lactocare group compared to the control group (p= 0.289). The mortality rate was 30% in the control group compared to 20% in the Lactocare group (p: 0.465).

 This study showed a remarkable effect of the probiotic preparation on the gut microbiota in critically ill septic patients as it decreased the number of opportunistic pathogens. However, additional clinical research is needed to translate research into clinical practice to refine the clinical indication of the specific probiotic strains.

 Dyslipidemia and diabetes mellitus are two important risk factors for coronary artery disease and stroke. Traditionally, herbal remedies like walnut were used to treat dyslipidemia. The study aimed to evaluate the effect of Juglans regia L. (J. regia L.) internal septum extract (ISE) on lipid profile of patients with type 2 diabetes.

 After preparing hydroalcoholic ISE, Folin-Ciocalteau (FC) and AlCl3 colorimetric methods were used to determine total phenolic content (TPC) and total flavonoid content (TFC), respectively. In a randomized, double-blind placebo-controlled trial, 86 diabetic patients with dyslipidemia were randomly divided into equal groups and received ISE or placebo capsules 1500 mg/day for 12 weeks. Lipid profile, LFT, SCr, urea, hemoglobin A1c (HbA1c), blood pressure (BP), weight, waist and waist to hip ratio (WHR) were determined at baseline and after 12 weeks. The paired sample t-test and independent sample t-test were performed to compare the differences within and among the groups, respectively. This study was registered in the Iranian registry of clinical trials (IRCT ID: IRCT20201227049850N1).

 The mean (SD) of TPC and TFC were measured based on 74.57 (5.20) milligram gallic acid equivalent/gram of dry extract (mg GAE/g DE) and 14.11 (2.73) mg quercetin equivalent/g of DE (mg QE/g DE), respectively. During the trial, 26 patients lost follow-up, and the study continued with remaining 60 patients. After intervention, there were no significant differences in LDL-C (p=0.44), total cholesterol (TC) (p=0.42), high-density lipoprotein cholesterol (HDL-C) (p=0.99), triglyceride (TG) (p =0.32) and Lp(a) (p=0.55) between two groups. Moreover, no significant (p>0.05) changes were observed in HbA1c, LFT, SCr, urea, BP, weight, waist, and WHR among the groups after 12 weeks.

 Our findings showed J.regia L. ISE had no significant effect on lipid profile compared to placebo. Moreover, no adverse effect was observed on liver and kidney function tests.

 Ursane triterpenoids could be considered as novel multi-target therapeutic anti-cancer agents. Salvurmin A and Salvurmin B are novel cytotoxic ursane triterpenoids isolated from the aerial parts of Salvia urmiensis, an endemic plant species of Iran.

 In this study, we assessed cytotoxicity of these compounds against two human cancer cell lines and one human normal cell line and investigated its mechanism via apoptosis and cell cycle arrest.

 Salvurmin A and B showed the most cytotoxic effect on A549 cells compared to other studied cancer cells. IC50 values for Salvurmin A and B against A549 cells were 35.6 ± 1.5 and 19.2 ± 0.8 µM, respectively. Based on annexin V staining, both of these compounds significantly induced apoptosis in A549 cells. Moreover, these two compounds significantly increased cell accumulation in G2/M and decreased the number of cells in G0/G1 phases in A549 cells in a dose-dependent manner.

 Based on the results Salvurmin B can be considered as potential candidate for further studies against human lung carcinoma.

 6-Hydroxydopamine (6-OHDA) is widely used to induce neurotoxicity and investigate the mechanisms of Parkinson disease. 6-OHDA causes cell injury through various mechanisms including oxidative stress, inflammation and apoptosis. The selective Rho-kinase inhibitor, fasudil displays neuroprotective effects in several neurodegenerative disorders. The aim of this study was to assess the protective effect of fasudil in PC12 cytotoxicity induced by 6-OHDA.

 PC12 cells were exposed to 5, 10, 25, and 50 µM of fasudil concentrations. After 24 h, the IC50 value of 6-OHDA (150 µM) was added. Twenty-four hours later, the viability of cells was evaluated via MTT assay and the formation of reactive oxygen species (ROS) was measured by the fluorimetric method. At the 50 µM concentration of fasudil, with or without 6-OHDA, the changes of protein levels including STAT3, P-STAT3, JAK2, P-JAK2, and caspase-3 were determined via western blotting.

 Our results showed that 6-OHDA increased the intracellular level of ROS, reduced cell viability, upregulated p-STAT3/STAT3 and p-JAK2/JAK2 ratios and significantly raised cleaved caspase-3 in comparison to control group. Furthermore, pretreatment of cells with fasudil (50 µM) for 24 h could reverse all changes induced by 6-OHDA.

 6-OHDA caused cytotoxicity in PC12 cells through inducing oxidative stress and activating JAK/STAT and apoptosis pathways, while pretreatment with fasudil exhibited protective effect on 6-OHDA-induced neurotoxicity via the inhibition of oxidative stress and prevention of these pathways.

 Recently, niosomes are becoming popular in drug delivery. The current work aimed to investigate the characteristics, cellular safety, and antifungal activity of ketoconazole-loaded niosome (ketosome).

 Ultrasonic approach was employed to prepare ketosome including cholesterol, nonionic surfactant and ketoconazole. The size characteristics and morphological features of ketosome and physicochemical properties of ketoconazole in ketosomes were evaluated using dynamic light scattering (DLS), differential scanning calorimetry (DSC), powder x-ray diffractometer (PXRD), scanning electron microscopy (SEM), and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. Also, the dissolution rate, cellular safety test and antimycotic properties of ketosome were examined.

 According to the results, the particle size of the ketosome decreased from 491.400±10.622 to 121.300±7.274 nm by the increment of cholesterol. According to further research, changes in the cholesterol:surfactants ratio can modulate the zeta potential from -27.866±1.069 to -12.500±1.153 mV. The highest entrapment of ketoconazole was about 87% when the cholesterol concentration in the ketosome was high. Ketosome with the maximum cholesterol:surfactants ratio showed the fastest drug release. Furthermore, the cell viability assay revealed that the ketosome had lower cytotoxicity in comparison with pure drug. The cell viability of the ketosome was estimated to be about 90% (HGF cell line). The ketosome had a lower MIC than the pure drug when tested against Candida albicans.

 The results of this study revealed that the optimized ketoconazole-loaded niosome could be used as a possible nanovesicle for ketoconazole drug delivery, potentially opening up new ways for the management of cutaneous candidiasis complaints.

 Letrozole is a non-steroidal drug utilized as a treatment of hormone-sensitive breast cancer. It has been shown that letrozole has harmful side effects. Therefore, it seems necessary to design a letrozole drug sensor. In this work, we scrutinized the sensing properties of the B30N30, AlB29N30, and GaB29N30 nanoclusters toward the letrozole drug in various adsorption sites.

 Investigations were done using the density functional theory (DFT) calculation with the B3PW91/6-311G(d, p) level of theory. The time-dependent density functional theory (TD-DFT) calculations were used to investigate Ultraviolet-visible (UV-vis) spectrums with the same level of theory.

 The adsorption energy of B30N30, AlB29N30, and GaB29N30 in the most stable complexes were calculated at -16.81, -34.62, and -27.41 kcal mol-1, respectively. The results obtained from the study of electronic properties showed a high sensitivity for the detection of letrozole in B30N30 compared to AlB29N30 and GaB29N30. The calculated recovery time for the B30N30 is 0.13 × 10-5 s, which indicates a very short recovery time. The UV-vis spectrums showed that the letrozole/B30N30 exhibits shift toward the higher wavelengths (red shift).

 Therefore, these results showed that the B30N30 is a good candidate for identifying letrozole. Further, B30N30 would be more effective than AlB29N30 and GaB29N30 due to the simple synthesis.

To discover the optimal solvent amounts for using in a particular application, it is vital to achieve some useful information in regard with suitable neat or mixed solvent and drugs equilibrium solubility in them. It is known that the low solubility of drugs such as bosentan (BST) in water negatively effects in vitro and in vivo kinetics of dissolution, affecting in turn its bioavailability along with making several difficulties around designing its liquid formulations.

Solubility of BST in some mixtures of polyethylene glycol 400 (PEG 400) and water was experimentally determined at T = (293.15 to 313.15) K by using a common shake-flask technique followed by UV-visible spectroscopic method. The experimental solubility data in PEG 400 mass fraction (w1) of 0.0 to 1.0 at 298.15 K and in w1=0.0, 0.5 and 1.0 at other temperatures were then correlated by cosolvency models including the Jouyban-Acree, the Jouyban-Acree-van’t Hoff, and the double log-log models and some un-measured solubility data were predicted based on the obtained trained models.

The results presented that the aqueous solubility of BST is increased by increasing mass fraction of PEG 400 as well as increasing temperature and reached the maximum value in neat PEG 400 at 313.15 K.

The BST solubility in water improved by addition of PEG 400 into it. According to the average relative deviations obtained from the back-computed data with trained models which were < 8.0%, it concluded that the selected models were able to predict the un-measured data with high reliability.

 Pyrazolyl borate derivatives are versatile ligands that can be coordinated with transition metals and formated a variety of different coordination modes. Copper complexes are highly active in biological applications and have high bioactivity. Because of the above description and applications, in the present work, synthesis and characterization of pyrazolyl borate derivative ligands and their Cu(II) complex were reported. The structure of the synthesized complex was determined by X-ray crystallography. In addition, the antimicrobial activity of the synthesized compounds along with the molecular docking of them was investigated.

 N-donor pyrazolyl borate derivative ligands abbreviated as K[HB(PzMe2)3] and K[H2B(PzMe2)2] and their Cu(II) complex were synthesized and characterized. The synthesized ligands and complex were evaluated for antibacterial activities against the gram-positive (B. subtilis) and the gram-negative (S. enterica) bacteria. Also, their molecular docking with B. subtilis SMC head domain (PDB ID: 5H67) as the possible targets was investigated.

 The in vitro and in silico results showed, among the investigated compounds, complex [Cu(H2B(PzMe2)2)(HB(PzMe2)3)] indicated the highest antibacterial activity. Also, the Statistical analysis showed that the difference between the obtained data was significant.

 We have synthesized N-donor pyrazolyl borate derivatives and their copper (II) complex. Single X-ray results indicated the Cu(II) complex adopted an N5 environment around the metal center with a distorted square pyramidal geometry. The obtained binding energy of molecular docking studies is in direct correlation with the in vitro antibacterial studies. Briefly, the reported Cu(II) complex may be considered as a potential antibacterial candidate.

 Benzo(α)pyrene (BaP) is one of the most familiar polycyclic aromatic hydrocarbons (PAHs) to evaluate food safety and quality and can be present in infant formulas An analytical method for the extraction and quantification of BaP in infant formula milk has been established by dispersive liquid–liquid microextraction (DLLME) followed by high-performance liquid chromatography with fluorescence detector.

 BaP was first extracted from matrices of infant formula milk via acetonitrile and then DLLME was used for further purification and preconcentration of target analyte.

 Under the optimum extraction conditions, 150 µL of dichloromethane as extraction solvent, 3 mL acetonitrile as disperser and cleaner solvent and 1 mL volume sample, the accuracy of the method was between 89-97%. The limits of detection and quantification were 0.12 and 0.35 ng/ml, respectively. There was a linear relation (R2=0.998) between chromatographic peak area and concentrations in the range of 0.5 to 15 ng/mL.

 The proposed method is applicable to the quantification of BaP in infant formula milk with acceptable accuracy and precision.