Cardioprotective Effect of Rumex vesicarius Linn. Leaf Extract against Catecholamine-Induced Cardiotoxicity

Rumex vesicarius (L.) is a folklore medicinal herb that has been used for centuries to cure cardiovascular diseases. The present work was carefully designed to ascertain the pharmacological basis for R. vesicarius’s therapeutic efficacy in cardiovascular diseases, as well as the underlying mechanism. In the ex vivo investigation, the aqueous-methanolic leaf extract of R. vesicarius was shown to have endothelium-dependent vasorelaxant effects in rabbit aorta tissue preparations, and its hypotensive responses were quantified by pressure and force transducers coupled to the Power Lab Data Acquisition System. Furthermore, when rabbits were subjected to adrenaline-induced myocardial infarction, R. vesicarius demonstrated cardioprotective characteristics. In contrast to the intoxicated group, the myocardial infarction model showed lower ALP, CK-MB, CRP, LDH, ALT, troponin, and AST levels (p > 0.005–0.000), as well as edema, necrosis, apoptosis, inflammatory cell enrolment, and necrosis. R. vesicarius exhibited significant antioxidant activity and delayed noradrenaline-induced platelet aggregation. Its cardioprotective, anticoagulant, and vasorelaxant properties in both investigations (in vivo and ex vivo) are mediated through partial endothelium-dependent, NO and calcium channel blockade mediated vasorelaxation. The minimizing of adrenaline, oxidative stress, and tissue damage demonstrate its therapeutic efficacy in cardiovascular diseases.     

The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study

In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position 4a–n. The structure of the newly prepared compounds was proved by microanalysis, IR, ¹H-NMR, ¹³C-NMR and mass spectral data. All the synthesized compounds were evaluated for their in vitro cytotoxic activity in numerous cancer cell lines including A549, HepG-2, LoVo and MCF-7 and normal HUVEC cell line. The two most active compounds 4d and 4f were then tested for their apoptosis induction using DNA content and Annexin V-FITC/PI staining. Moreover, apoptosis initiation was also confirmed using RT-PCR and Western blot. To further understand the binding preferences of quinazoline sulfonamides, docking simulations were used. Among the fourteen new synthesized compounds, we found that compounds 4d and 4f exerted the strongest cytotoxicity against MCF-7 cells with an IC₅₀ value of 2.5 and 5 μM, respectively. Flow cytometry data revealed the ability of compounds 4d and 4f to mediate apoptosis and arrest cell cycle growth at G1 phase. Furthermore, RT-PCR and Western blot results suggested that both 4d and 4f activates apoptotic cell death pathway in MCF-7 cells. Molecular docking assessments indicated that compounds 4d and 4f fit perfectly into Bcl2’s active site. Based on the biological properties, we conclude that both compounds 4d and 4f could be used as a new type of anticancer agent, which provides a scientific basis for further research into the treatment of cancer.     

Spectrophotometric and spectrodensitometric quantification of a new antiviral combination

Accurate, simple, and selective spectrophotometric and spectrodensitometric methods were developed and adopted to quantify velpatasvir (VPS) and sofosbuvir (SFV) concurrently in their pure forms and tablets. The spectrophotometric technique was based on the first derivative of ratio spectra (¹DD) technique and developed to determine VPS and SFV simultaneously in table formulation. However, the spectrodensitometric technique was based on thin-layer chromatography (TLC) and densitometry and developed to determine VPS and SFV simultaneously in tablet dosage form. Chromatographic separation was performed using chloroform:methanol 9.5:0.5 (%, v/v) as the mobile phase on glass-coated TLC plates. Detection was achieved using a 265-nm deuterium lamp in absorbance mode. Both analytical methods were validated according to the International Conference on Harmonization (ICH)-Q2B guidelines. The linearity in the range of concentration ranges of 1–50 μg/mL and 5–80 μg/mL were obtained for VPS and SFV, respectively, using ¹DD spectrometric method. However, the linearity in the range of 5–50 and 10–70 μg/band for VPS and SFV, respectively, were recorded using TLC–densitometric method. Accuracy was recorded ˃100% for VPS and SFV using both methods. This is the first TLC–densitometry method that can separate and quantify the studied mixture of the drugs. The proposed analytical methods were found to be accurate, precise, selective, robust and sensitive for simultaneous analysis of VPS and SFV in tablet dosage forms.

     

In Vitro Alpha-Amylase and Alpha-Glucosidase Inhibitory Activity and In Vivo Antidiabetic Activity of Withania frutescens L. Foliar Extract

Withania frutescens L. is a wild perennial woody plant used by the local population for diverse therapeutic purposes. This work aims to study for the first time the potential inhibitory effect of this plant hydroethanolic extract on α-amylase and α-glucosidase activities using in vitro methods and its antidiabetic and antihyperglycemic activities using alloxan-induced diabetic mice as a model for experimental diabetes. Two doses were selected for the in vivo study (200 and 400 mg/kg) and glibenclamide, a well-known antidiabetic drug (positive control) in a subacute study (28 days) where the antihyperglycemic activity was also assessed over a period of 12 h on diabetic mice. The continuous treatment of diabetic mice with the extract of Withania frutescens for 4 weeks succeeded to slowly manage their high fasting blood glucose levels (after two weeks), while the antihyperglycemic test result revealed that the extract of this plant did not control hyperglycemia in the short term. No toxicity signs or death were noted for the groups treated with the plant extract, and it shows a protective effect on the liver and kidney. The in vitro assays demonstrated that the inhibition of alpha-amylase and alpha-glucosidase might be one of the mechanisms of action exhibited by the extract of this plant to control and prevent postprandial hyperglycemia. This work indicates that W. frutescens have an important long term antidiabetic effect that can be well established to treat diabetes.     

Development of GBRT Model as a Novel and Robust Mathematical Model to Predict and Optimize the Solubility of Decitabine as an Anti-Cancer Drug

The efficient production of solid-dosage oral formulations using eco-friendly supercritical solvents is known as a breakthrough technology towards developing cost-effective therapeutic drugs. Drug solubility is a significant parameter which must be measured before designing the process. Decitabine belongs to the antimetabolite class of chemotherapy agents applied for the treatment of patients with myelodysplastic syndrome (MDS). In recent years, the prediction of drug solubility by applying mathematical models through artificial intelligence (AI) has become known as an interesting topic due to the high cost of experimental investigations. The purpose of this study is to develop various machine-learning-based models to estimate the optimum solubility of the anti-cancer drug decitabine, to evaluate the effects of pressure and temperature on it. To make models on a small dataset in this research, we used three ensemble methods, Random Forest (RFR), Extra Tree (ETR), and Gradient Boosted Regression Trees (GBRT). Different configurations were tested, and optimal hyper-parameters were found. Then, the final models were assessed using standard metrics. RFR, ETR, and GBRT had R2 scores of 0.925, 0.999, and 0.999, respectively. Furthermore, the MAPE metric error rates were 1.423 × 10⁻¹ 7.573 × 10⁻², and 7.119 × 10⁻², respectively. According to these facts, GBRT was considered as the primary model in this paper. Using this method, the optimal amounts are calculated as: P = 380.88 bar, T = 333.01 K, Y = 0.001073.     

Powerful Antioxidants and Cytotoxic Activities of the Methanol Extracts from Eight Soybean Cultivars

In the present study, the chemical composition and total phenolic (TPC) and total flavonoid contents (TFC) of eight soybean cultivars (Giza 21, Giza 22, Giza 35, Giza 111, Giza 82, Giza 83, Crawford, and Holliday) were estimated. Moreover, antioxidant activity and in vitro cytotoxic activities against HepG-2 and MCF-7 were evaluated. Giza 21, Giza 111, and Crawford cultivars recorded higher than 40% crude protein. The analysis revealed that TPC values in seed extracts ranged from 10.5 mg GAE/g extract in Giza 35 to 6.4 mg GAE/g extract in Giza 22. TFC varied from 1.20 mg QE/g extract in Giza 111 to 0.55 mg QE/g extract in Crawford. Giza 35 exhibited the highest content of genistein and daidzein and the highest free radical scavenging activity (61.833%). The results of the MTT assay demonstrated that the soybean methanolic extracts inhibited the proliferation of HepG-2 and MCF-7 cells in a dose-dependent manner. Giza 35 exhibited the highest cytotoxic activity. In conclusion, Giza 35 cultivar recorded the highest TPC and TFC values and antioxidant and cytotoxic activities. Therefore, this cultivar can be used as a source for the production of pharmaceutical and medicinal products rather than as a nutritional source of protein.     

Self-Nanoemulsifying Drug Delivery System (SNEDDS) of Apremilast: In Vitro Evaluation and Pharmacokinetics Studies

Psoriatic arthritis is an autoimmune disease of the joints that can lead to persistent inflammation, irreversible joint damage and disability. The current treatments are of limited efficacy and inconvenient. Apremilast (APR) immediate release tablets Otezla^® have 20–33% bioavailability compared to the APR absolute bioavailability of 73%. As a result, self-nanoemulsifying drug delivery systems (SNEDDS) of APR were formulated to enhance APR’s solubility, dissolution, and oral bioavailability. The drug assay was carried out using a developed and validated HPLC method. Various thermodynamic tests were carried out on APR-SNEDDS. Stable SNEDDS were characterized then subjected to in vitro drug release studies via dialysis membrane. The optimum formulation was F9, which showed the maximum in vitro drug release (94.9%) over 24 h, and this was further investigated in in vivo studies. F9 was composed of 15% oil, 60% S_mix, and 25% water and had the lowest droplet size (17.505 ± 0.247 nm), low PDI (0.147 ± 0.014), low ZP (−13.35 mV), highest %T (99.15 ± 0.131) and optimum increases in the relative bioavailability (703.66%) compared to APR suspension (100%) over 24 h. These findings showed that APR-SNEDDS is a possible alternative delivery system for APR. Further studies are warranted to evaluate the major factors that influence the encapsulation efficiency and stability of APR-containing SNEDDS.     

Salivary MMP-9 Levels in Chronic Periodontitis Patients with Type-II Diabetes Mellitus

Chronic periodontitis and diabetes mellitus share a two-way relationship, the common factor being the inflammatory-mediated pathway, and various cytokines are released during this inflammatory cascade, one of which being matrix metalloproteinase-9. The aim of this study was to identify whether the levels of matrix metalloproteinase-9 are increased due to type-II diabetes mellitus in chronic periodontitis patients. It was an observational, analytical, case-control study. Thirty subjects were recruited in the test group, who were suffering from type-II diabetes mellitus and chronic periodontitis, and 30 subjects in the control group, who were subjects with chronic periodontitis but systemically healthy. Periodontal parameters, including the plaque score, gingival bleeding index, probing pocket depth and clinical attachment level of the subjects, were measured, saliva samples of all of the subjects were collected and salivary matrix metalloproteinase-9 levels were analyzed by an enzyme-linked immunosorbent assay (ELISA) technique. The statistical analysis was performed using SPSS 24. Overall, the matrix metalloproteinase-9 levels of the diabetic patients with chronic periodontitis were increased almost twofold (156.95 ± 29.80 ng/mL) compared to the levels in the controls (74.96 ± 6.32 ng/mL) (p < 0.001). Similarly, the periodontal parameters were far worse in diabetics with chronic periodontitis compared to the controls. The average gingivitis score for the test subjects was 78.45 ± 8.93%), compared to 29.32 ± 12.96% in the controls (p < 0.001). The mean probing pocket depth for the test group was 5.39 ± 0.60 mm, and, for the control group, it was 4.35 ± 0.31 mm (p < 0.001). For the test subjects, the average clinical attachment level was 5.86 ± 0.58 mm, and it was 4.66 ± 0.32 mm for the controls (p < 0.001). It was ascertained that there is a two-fold increase in the levels of salivary matrix metalloproteinase-9 in the test group compared to the control group. In addition, the level of periodontal apparatus destruction was greater in the test group. This proved that type-II diabetes mellitus influences the levels of matrix metalloproteinase-9 in humans and elevates them, causing further periodontal destruction.     

Superfast Synthesis of Stabilized Silver Nanoparticles Using Aqueous Allium sativum (Garlic) Extract and Isoniazid Hydrazide Conjugates: Molecular Docking and In-Vitro Characterizations

Green synthesis of silver nanoparticles (AgNPs) was synthesized from fresh garlic extract coupled with isoniazid hydrazide (INH), a commonly used antibiotic to treat tuberculosis. A molecular docking study conducted with the selected compounds compared with anthranilate phosphoribosyltransferase (trpD) from Mycobacterium tuberculosis. The aqueous extract of garlic was prepared and mixed with silver nitrate (AgNO3) solution for the superfast synthesis of stable AgNPs. INH was then conjugated with AgNPs at different ratios (v/v) to obtain stable INH-AgNPs conjugates (AgNCs). The resulting AgNCs characterized by FTIR spectra revealed the ultrafast formation of AgNPs (<5 s) and perfectly conjugated with INH. The shifting of λmax to longer wavelength, as found from UV spectral analysis, confirmed the formation of AgNCs, among which ideal formulations (F7, F10, and F13) have been pre-selected. The zeta particle size (PS) and the zeta potential (ZP) of AgNPs were found to be 145.3 ± 2.1 nm and −33.1 mV, respectively. These data were significantly different compared to that of AgNCs (160 ± 2.7 nm and −14.4 mV for F7; 208.9 ± 2.9 nm and −19.8 mV for F10; and 281.3 ± 3.6 nm and −19.5 mV for F13), most probably due to INH conjugation. The results of XRD, SEM and EDX confirmed the formation of AgNCs. From UV spectral analysis, EE of INH as 51.6 ± 5.21, 53.6 ± 6.88, and 70.01 ± 7.11 %, for F7, F10, and F13, respectively. The stability of the three formulations was confirmed in various physiological conditions. Drug was released in a sustainable fashion. Besides, from the preferred 23 compounds, five compounds namely Sativoside R2, Degalactotigonin, Proto-desgalactotigonin, Eruboside B and Sativoside R1 showed a better docking score than trpD, and therefore may help in promoting anti-tubercular activity.