Current Pharmaceutical Design - Online First

Rumex nervosus Vahl is a phenomenal plant from Arabian Peninsula and East African areas. It potentially contains massive therapeutic phytochemicals, including Omeprazole, sitosterols, fatty acids, flavonoids and carotenes. Omeprazole (a commercial drug) is used to treat stomach ulcers, gastroesophageal reflux and cardiac disorders. Beta-sitosterol (commercial drug) reduces cholesterol levels and body swelling. It is also known to manage rheumatoid arthritis.

The present study evaluated the pharmacological potential and metabolite profiling of Rumex nervosus through various extracts. The extraction was performed using different solvents (Petroleum ether, Chloroform, n-Hexane, Butanol, Methanol, and distilled water) through soxhlet extraction method. Serial dilutions of (100-3.125 mg/mL) were prepared. The biological activities, antimicrobial, anti-diabetic, Hemolytic, anti-inflammatory, and antioxidant (DPPH radical Scavenging, Total anti-oxidant and total phenolic content assays) were performed. Statistical analysis of experimental data was carried out by using SPSS Version 20 and Origin 6.0. Data was represented as mean ± standard deviation (n=3). Differences among mean values were determined using Two-way ANOVA and Tukey’s test. The level of statistical significance was set at p ≤ 0.05. The potential extracts were further analyzed for phytochemicals through GC-MS and Network pharmacology (In silico approach).

The plant exhibited the best antioxidant activity (86.7% ± 1.92) at 100 mg/mL with distilled water extract. The highest anti-inflammatory activity (90.64 ± 2.34) (88.31 ± 2.37) was given by n-butanol and distilled water extracts at 100 mg/mL. The optimum anti-diabetic activity (92.78 ± 1.89) was observed at 100 mg/mL with n-butanol.

The maximum zone of inhibition was measured with n-butanol extract against Pseudomonas aeruginosa (36.67 ± 0.32) at 100 mg/mL, and in the case of Xanthomonas oryzae again n-butanol extract showed maximum zone of inhibition (30.47 ± 0.32) at 100 mg/mL. The maximum fungal zone of inhibition (22.33 ± 0.40) was noticed with n-butanol extract against Fusarium oxysporom at 100 mg/mL, and in the case of Aspergillus niger maximum fungal zone of inhibition was measured with n-butanol extract (16.20 ± 0.25) at 100 mg/mL. Hemolysis activity was highest (4.12 ± 0.01) with the methanol extract at 3.125 mg/mL. R. nervosus displayed the best activities with n-butanol and distilled water extract. GCMS and network pharmacology combined approach identified seven phytochemicals associated with oxidative stress and infectious diseases (1-Tetradecanol, Stigmast-5-ene, Phthalic acid 2-ethylhexyl isohexyl ester, A-Norcholestan-3-one, 5-ethenyl-, (5.beta.), 16-Heptadecenal, gamma-Sitosterol, Omeprazole). Degree score method selected 10 top hub genes, including AKT1, TNF, and EGFR, as potential targets for the identified phytochemicals. Omeprazole and 1-Tetradecanol are currently being used as medicines for treating gastric problems and inflammation.

R. nervosus has been confirmed as a potential source of these compounds through a multifaceted approach, hence it could thus be considered a safe, significant therapeutic source.

Ovarian cancer (OC) is a common malignant tumor of the female reproductive system and is usually found at an advanced stage. However, the treatment of OC with conventional the efficacy of surgery and chemotherapy is limited. Brusatol (BRU) is a unique nuclear factor erythroid 2-related factor 2 (Nrf2) pathway inhibitor with significant anti-cancer effects. At the same time, the Nrf2 system also plays a vital role in ferroptosis, which can be used as a new way to treat tumors. This study investigated the mechanism of action of BRU as a novel ferroptosis inducer to inhibit OC cells.

Using bioinformatics to screen for key targets and pathways that act on OC in BRU, and then the effects of BRU on OC cells were examined by cell viability assay, clone formation assay, wound healing assay, and apoptosis assay. The intracellular levels of ROS (Reactive Oxygen Species), Fe²⁺, glutathione (GSH), and malondialdehyde (MDA) were also quantified. Western blotting analysis was then performed to verify ferroptosis marker proteins and pathways. In addition, the combination of Ferrostatin-1 (Fer-1) and BRU was further tested for ferroptosis-related markers.

By obtaining BRU and OC targets, 171 potential BRU-OC action targets were screened to the core target NQO1. KEGG enrichment analysis showed that the anticancer effects of IBC were mediated through multiple pathways, including the PI3K-AKT and Ras signaling pathways. In vitro results showed that IBC inhibited the proliferation, invasion, and migration of OC cells and induced ferroptosis in OC cells.

We demonstrated that BRU increased intracellular ROS, Fe^2+, and MDA levels. It also significantly reduced intracellular GSH level and the expression of two marker proteins for ferroptosis, GPX4 and SLC7A11. Meanwhile, BRU could inhibit the Nrf2/HO-1/NQO1 and AKT/mTOR dual signaling pathways in OC cells. Furthermore, the combination of Ferrostatin-1 (Fer-1) and BRU reversed BRU-induced ferroptosis in OC cells.

In this study, we demonstrated for the first time through bioinformatics, molecular docking technology, and experimental validation that BRU acts as a novel inducer of ferroptosis in ovarian cancer cells by targeting the Nrf2/HO-1/NQO1 and AKT/mTOR dual signaling pathways, and may have great potential in the treatment of ovarian cancer cells.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are among the most effective treatments for type 2 diabetes mellitus (T2DM). GLP-1 RAs stimulate pancreatic receptors, improving glycemia by boosting insulin secretion while decreasing glucagon secretion. GLP-1 receptors are present in pancreatic tissue. They are also found in extra-pancreatic tissue and have been shown to reduce body weight while also protecting the heart and endothelial cells. The most prevalent types of GLP-1 RAs can be injected twice daily (exenatide), once daily (lixisenatide and liraglutide), or once weekly (albiglutide, dulaglutide, exenatide once, semaglutide, tirzepatide). GLP-1 receptor agonists also reduce gastric emptying, preventing substantial post-meal glycaemic increases. Many publications have been written regarding GLP-1 RAs, covering various features of this family. However, the purpose of this study is to investigate the pharmacological design models and pharmacokinetic characteristics of the most regularly used members of this class, as well as to highlight contemporary developments in GLP-1 RAs. It also describes the physicochemical features, techniques of manufacture, the effects of molecular structure, and structural modifications on pharmacological activity.

The literature review was completed using a structured approach to identify and integrate relevant literature. It involved a broad search of reputable medical databases using inclusion and exclusion criteria.

They are classified as short-acting or long-acting based on the length of their action. Short-acting GLP-1 RAs and long-acting GLP-1 RAs have differing efficacy profiles. Furthermore, the methods of administration, mode of action, and side effects of these medications are relevant to their pharmacological design and pharmacokinetic properties.

The treatment of type 2 diabetes and obesity has evolved with the advent of GLP-1 RAs. These drugs have a multifaceted approach, emphasizing glycemic regulation, weight loss, and reduction of cardiovascular risk. Their unique mode of action, strong safety profile, and ability to be individualized according to each patient's needs make them a valuable therapeutic option in the management of metabolic disorders. Their pharmacological activities are also influenced by their different structural and pharmacokinetic properties.

GLP-1 RAs have a complex strategy due to their pharmacological nature. The variations in their design have led to various members with varying pharmacodynamic and pharmacokinetic features.

Endometriosis is a widespread estrogen-driven condition causing pelvic pain and infertility in women. This disease shares five features with cancer: Intrinsic growth signals, insensitivity to anti-proliferative signals, impaired apoptosis, induction of angiogenesis, and heightened tissue invasion, suggesting common therapeutic targets for both conditions. This article reviews studies investigating the anti-cancer drugs' protective effects and mechanisms in endometriosis treatment, providing essential insights into their efficacy and the relevant pathways in managing the disease.

A comprehensive review was conducted to assess the potential therapeutic benefits of anti-cancer drugs in endometriosis treatment. This included an extensive search of Google Scholar and PubMed, using relevant keywords without any limitations untilthe end of 2024, to ensure a thorough analysis of existing research in this field.

Many drugs used in treating estrogen-dependent and other cancers have demonstrated significant therapeutic potential for endometriosis, as supported by cellular, animal, and clinical studies.

Though these drugs may have significant side effects, more research is necessary to determine their usefulness in endometriosis treatment. By studying various drug dosages and regimens, researchers can aim to achieve effective treatment with minimal side effects. Personalized treatment based on illness severity can be achieved by selecting the right medication and dosage.

Future research can include optimizing dosages in preclinical studies, comparing repurposed drugs to conventional therapies in randomized trials, and conducting longer and larger clinical trials further to assess side effects and effectiveness in endometriosis patients.

The combination of Astragalus membranaceus and Safflower (AS) is known for its efficacy in benefiting Qi and activating blood circulation, making it a frequently used empirical combination in traditional Chinese medicine. Numerous reports have highlighted the interventional effect of this combination in treating ischemic stroke (IS). However, the active ingredients and potential mechanisms underlying its treatment of stroke have not been fully elucidated.

Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), along with various data processing methods, were utilized to identify and assess the chemical constituents in rat serum following AS gavage administration. Chemical constituent targets were predicted using the SEA and Swiss Target Prediction databases, while IS-related targets were sourced from the GeneCards, OMIM, and TTD databases. The intersecting targets of constituents and diseases were screened, and a core target network map was constructed using the String database and Cytoscape software. KEGG pathway enrichment of core targets was analyzed using DAVID and Metascape databases. The middle cerebral artery occlusion (MCAO) rat model was established to evaluate the cerebroprotective effects of AS. The accuracy of predicted pathways was validated using immunofluorescence (IF) and Western blot (WB) analyses.

Thirty-five ingredients in serum were identified, and 437 targets and 3748 IS-related targets were identified, 291 of which overlapped. Protein-protein interaction (PPI) analysis predicted 15 major targets, including TNF and MAPK3. KEGG pathway analysis indicated that the MAPK/NF-κB and VEGF/Notch1 signaling pathways may play pivotal roles in the therapeutic effects of AS in IS. Moreover, AS significantly ameliorated neurological and motor function impairments, as well as brain histopathological damage, in MCAO rats. AS treatment led to reduced levels of the inflammatory cytokines IL-6 and TNF-α, inhibited astrocyte hyperactivation, decreased nuclear translocation of NF-κB p65, reduced expression of p-MAPK (Erk1/2)/ MAPK (Erk1/2) and p-NF-κB (p65)/NF-κB (p65) proteins, increased the number of CD31⁺/Ki67⁺ and VEGF⁺/ Ki67⁺-positive vessels, and upregulated the expression of VEGF, VEGFR-2, Notch1, and DLL4 proteins.

AS may regulate MAPK/NF-κB and VEGF/Notch1 pathways to reduce inflammation and promote post-ischemic neovascularization, providing a promising method for the treatment of ischemic stroke.

The progressive neurodegenerative disease known as Alzheimer's disease (AD) is typified by neuroinflammation, amyloid-beta buildup, and cognitive impairment. Current pharmacological treatments merely alleviate symptoms, despite extensive research, which underscores the need for innovative, multi-target medicines. Since apolipoprotein E4 (ApoE4) is a significant genetic risk factor linked to the development of AD, it is a potentially effective treatment target. With their neuroprotective qualities, natural substances like Ginkgolide may help treat some diseases. This study investigates Ginkgolide's potential as a multi-target treatment for AD, with a particular emphasis on how it interacts with the ApoE4 N-terminal domain.

The interaction between Ginkgolide and ApoE4 (PDB ID: 8AX8) was assessed using pharmacokinetic profiling, molecular docking, and molecular dynamics (MD) simulations. MD simulations were used to determine stability, and AutoDock Vina was used to obtain the binding affinity. To predict pharmacokinetics and toxicity, SwissADME and PkCSM were employed. The effectiveness of ginkgolide was contextualized using comparative docking with curcumin and resveratrol.

Ginkgolide formed sustained hydrophobic contacts with important sites and demonstrated a substantial binding affinity (-7.1 kcal/mol) to ApoE4. MD simulations verified negligible fluctuations and complex stability over 100 ns. Pharmacokinetics showed no significant toxicity risks, good gastrointestinal absorption, and favorable blood-brain barrier permeability. In terms of binding affinity and stability, ginkgolide fared better than curcumin and resveratrol, indicating its greater therapeutic potential.

The results indicate that ginkgolide effectively binds and stabilizes the ApoE4 N-terminal domain, supporting its potential role in modulating a key pathological factor in Alzheimer’s disease. Its superior pharmacokinetic profile and interaction dynamics compared to curcumin and resveratrol suggest a broader therapeutic relevance. These in silico insights provide a mechanistic basis for further investigation into ginkgolide’s neuroprotective effects.

The results demonstrated ginkgolide as a potentially effective multi-target treatment for AD through ApoE4 regulation. It is a better option than other natural chemicals because of its potent binding affinity, stability, and pharmacokinetics. These findings highlight the value of in silico methods in the early stages of drug discovery and the need for additional experimental support before they can be used in clinical settings.