Medicine in Drug Discovery最新文献

Controlling microorganism outbreaks is a critical challenge in preventing the spread of infectious diseases. In addition, an increase in drug-resistant bacterial strains came from cross-contamination and medication overuse, making the problem much more difficult to control. One of the most humongous obstacles to the efficient treatment of a wide range of common infections is antimicrobial resistance (AML-R). Currently, antibiotics are being used hugely to treat such infectious conditions. However, because of their synthetic nature, the development of resistance to them when used over a long period of time or in low doses prompts us to seek alternative treatments. Phytoactives or bioactives from plant sources are the natural solutions to these conditions, as Mother Nature has already provided the answer to every ailment that mankind has faced. The most effective therapies for AML-R have been derived from natural Phytoactives. Because of the abundance of biologically active molecules found in nature, it is by far the best alternative to treat any infections. However, the bioavailability, pharmacokinetic characteristics, low solubility, poor gastrointestinal absorption, low hydrophilicity, and delayed intrinsic dissolution are the major physicochemical barriers that hinder the utilization of these natural actives as AML treatments. These problems can be overcome through the application of novel drug-delivery technologies. This review provides a comprehensive study of AML Phytoactives-based drug delivery, leveraging the potential of nanotechnology to address and overcome the delivery problems associated with them, resulting in a successful approach toward antimicrobial therapy.

PE and GDM are two major metabolic diseases affecting pregnancy. Individuals suffering from GDM are at an increased risk of developing PE in later gestational stages. Current study was done to evaluate first trimester serum and urine metabolome using nuclear magnetic resonance (NMR) spectroscopy to identify metabolites and pathways differentially regulated in both diseases. Serum metabolomics analysis revealed deregulation in larger group of metabolites and pathways as compared to urine between PE/GDM and NT groups. Few metabolites showed altered expression in both aliments. Perturbed metabolites have association with energy metabolism, protein metabolism, insulin sensitivity, gut microbiome and maintenance of redox balance. Deregulation in these metabolic pathways contributes to the pathology of GDM/PE. Our study revealed that serum metabolomic profile of PE and GDM shows overlap in 1st trimester of gestation. It also explored the potential of NMR metabolomics in identification of common biomolecules that could be developed into a clinical tool for early detection of both PE /GDM.

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Ulcerative colitis and gastric ulcer are ulcers of gastrointestinal track, especially associated with elevated oxidative stress and inflammation. Dimethyl fumarate (DMF) is used for the treatment of multiple sclerosis and psoriasis and is considered useful in a variety of conditions associated with inflammation. We have investigated the effect of oral DMF (1, 10, 25, 50, 100, 200 mg/kg) in ethanol-induced gastric ulcers in rats. The effect of oral (15, 30, and 60 mg/kg) and intracecal (15 mg/kg) DMF was also investigated in dextran sulfate sodium (DSS)-induced colitis in mice. Treatment of DMF by oral route prevented the development of ethanol-induced gastric ulcers by decreasing oxidative stress in a dose-related manner. Oral and intracecal administration of DMF attenuated body weight loss, increase in disease activity score, colon length shortening, colon weight loss, inflammation and fibrosis, and decreased myeloperoxidase activity. Oral and intracecal DMF prevented a decrease in hemoglobin and suppressed oxidative stress, and also decreased MCP-1, IL-1ß, and IL-6 levels in the inflamed colon. Unlike oral DMF, intracecal DMF treatment did not reduce spleen weight. The effect of intracecal DMF was similar to the highest tested dose of oral DMF (60 mg/kg). These results demonstrated that intracecal DMF suppresses inflammation and oxidative stress in ethanol and DSS-induced colitis without alteration of spleen weight. This suggests that the localized DMF administration could be beneficial approach of treating gastrointestinal ulcers.

As a powerful tool for the discovery of peptide compounds, high-throughput library screening technology can also perform multitarget screening with high chemical diversity as a condition, which accelerates the process of exploring high-affinity peptide molecules. These techniques can be generally divided into in vitro and in vivo screening techniques, both of which play important roles in peptide drug discovery. Compared with linear peptides, cyclic peptides have been proven to have good bioavailability, membrane permeability, and stability and longer half-lives and have gradually become a topic of high interest in peptide drug research. High-throughput library screening technology plays an important role in the development of cyclic peptide drugs. Based on published studies, this paper reviews the high-throughput library screening technology used in the development of cyclic peptide drugs.

Ivermectin is a well-known and widely used anti-parasitic drug. Recently, in vitro data suggest anti-viral efficacy of the drug, albeit at much higher concentrations than currently approved. Despite warnings by several governing bodies, the (uncontrolled) human use of ivermectin has significantly increased during the COVID-19 epidemic. This study thus aimed to elucidate potential neurological risk of particularly the veterinary formulation of ivermectin in comparison to pure ivermectin. Zebrafish eggs (1hpf) and larvae (4dpf) were exposed to a range of concentrations of either pure ivermectin (IVM) or a veterinary formulation (V-IVM) for a period of 24 hours. Behavioral responses to both treatments were assessed at various timepoints using the pentylenetetrazol assay, the light–dark assay and a 5-day teratogenesis protocol. In addition, dissolution rates were calculated for both treatments. Acute responses of larvae at 4–<5dpf was similar for both treatments – a transient hyperlocomotion was followed by a general hypolocomotion (ANOVA dose effect, P < 0.01). Both IVM and V-IVM-treated larvae showed significant dose-dependent (ANOVA dose effect, P < 0.0001) decreases in responsiveness to repeated light–dark transitions, which again was more pronounced in IVM. These effects were maintained after 24 hours of exposure. In contrast, when ivermectin was administered prior to establishment of the blood brain-barrier in the teratogenesis protocol, V-IVM treatment was linked to more severe activity decline on <5dpf. Differences in dissolution rates cannot account for these differences. In conclusion, current data suggest significantly higher neurological risk of a veterinary formulation of ivermectin under conditions of penetration across the blood brain-barrier.

In malaria endemic countries, coinfections and cotransmissions of different viral pathogens are widely reported. Prior studies have shown that malaria can trigger the Epstein-Barr virus (EBV) reactivation in the body. Besides, the altered immunity due to malaria could increase susceptibility to acquire co-circulating viruses like SARS-CoV-2 or vice versa during pandemic times. The dual burden of pathogens can deteriorate health by inducing disease severity. There are no or limited antiviral therapies available against EBV and SARS-CoV-2. Exploring the novel antimalarials for checking antiviral efficacy and using them in such cases could be the efficient approach of ‘hitting two birds with one stone’. We investigated the antiviral potency of medicine for a malaria venture’s malaria box containing 400 drug-like or probe-like compounds with experimentally proven antimalarial activity. We utilized a molecular docking approach to screen these compounds against crucial proteins- EBNA1 of EBV and RdRp of SARS-CoV-2 respectively. Based on binding affinity we shortlisted the top three compounds for each protein. Further, for validation of complex stability and binding, the protein–ligand complex is subjected to 100 ns molecular dynamic simulation. All the compounds showed stable binding with respective proteins. Based on binding free energies, involvement of important residues from target sites, and ADMET properties of compounds, the top ligand for each protein is selected. Ligand B (MMV665879) for EBNA1 (ΔG_bind = -183.54 kJ/mol) and Ligand E (MMV665918) for RdRp (ΔG_bind = -172.23 kJ/mol) could act as potential potent inhibitors. These antimalarial compounds can hence be utilized for further experimental investigation as antivirals against EBV and SARS-CoV-2.

Colorectal cancer (CRC) is a common cancer in the world and also has a high death rate. It is reported that vaccination is a great strategy for CRC. CRC vaccines are based on CRC tumor antigens, including tumor-associated antigens like CEA, MUC-1, CTAs and tumor-specific antigens including personalized and shared neoantigen. Challenges emerge in vaccine design and therapeutic effect and combination with other anti-tumor therapies has recently become popular. This review is going to summarize the preclinical and clinical progress of CRC vaccines based on tumor antigens mentioned above, as well as challenges and future in this field.

As a “marker of self”, CD47 is expressed on the surface of all cells in humans, mice, and other mammals to inhibit phagocytic destruction of normal cells through interacting with signal regulatory protein α (SIRPα) on the macrophages and dendritic cells and sending a “don’t eat me” signal. Unfortunately, multiple types of cancer cells take advantage of this “don’t eat me” signal by overexpressing CD47 on their surface to evade recognition by the macrophages and avoid immune surveillance. Thus, the blockage of the CD47-SIRPα axis may be a promising therapeutic target for cancer therapy. However, CD47-targeted therapies can most likely cause serious side effects such as anemia due to the widespread expression of CD47 in normal tissues, thereby, the precise delivery of CD47-targeted therapeutics is a key part in increasing clinical efficacies and reducing side effects. In addition, the “don’t eat me” signal can also be exploited to design anti-phagocytic drug delivery systems to enhance circulation time in blood and accumulation in tumor sites. In this review, we focus on the two parts of CD47-SIRPα axis in the tumor therapy, one is the accurate delivery of CD47-targeted therapeutics by well-designed delivery systems, the other is the rational design of CD47 based anti-phagocytic drug delivery systems.

Aims

The aim of this study was to establish a model for prediction and early diagnosis of multiple sclerosis (MS) based on motion-dependent neurophysiological variables.

Main methods

The statistical population included 110 volunteers with and without MS in Mazandaran province, Iran. Based on the information provided by the subjects, they were assigned into the following groups; MS and control groups, and based on disease model they were further divided into relapsing-remitting (RR), progressive-relapsing (PR) and control groups, and according to the activity levels they were assigned into active MS, sedentary MS, active control and sedentary control groups. The Support Vector Machine (SVM) method was used to ensure separation and prediction accuracy. All calculations were performed using MATLAB software (version 2016).

Key findings

99.1% separation accuracy and 90% prediction accuracy were observed in non-kinematic data, while in kinematic and electromyography (EMG) data, this was 66% for separation accuracy and 65% regarding prediction accuracy. Among the measured variables, static balance and strength had the greatest effect on prediction results.

Significance

Using SVM technique and incorporating early symptoms of MS, we were able to achieve a high precision in predicting MS among the participants. Based on SVM, we achieved a considerably higher prediction accuracy extrapolated from non-kinematic dataset compared to kinematic and EMG datasets. Therefore, this study has opened up a great avenue towards predicting MS based on clinical parameters which could provide the clinicians with information regarding progression of the disease well in advance helping in opting for the best treatment strategies.

Objective

The aim of this study was to explore the therapeutic target and mechanism of Hydroxy Safflower Yellow A pigment (HSYA)—the main water-soluble component of Safflower—in the treatment of Poststroke Cognitive Impairment (PSCI) by network pharmacology and molecular docking methods.

Method

GeneCards, PharmMapper, and Swiss Target Prediction databases were used to screen HSYA targets. Protein-Protein Interaction analysis, Gene Ontology, and KEGG enrichment analysis were performed through STRING and Metascape databases, respectively. Cytoscape 3.6.0 was used to draw the network diagram of the “HSYA-target-PSCI pathway.” AutoDockVina was used for molecular docking.

Results

A total of 310 targets of HSYA and 2455 potential targets of PSCI were screened, and the shared target was 159. After GO and KEGG enrichment analysis, HSYA was found to exhibit a therapeutic effect on PSCI by regulating various cancer pathways, endocrine regulation, cell proliferation, and apoptosis pathways. The molecular docking results suggest that HSYA has the best docking activity with the core target HRAS. Molecular dynamics simulation results showed that HSYA was the best binding agent to MAPK1, followed by HRAS.

Conclusion

HSYA may regulate cell autophagy and apoptosis by regulating various pathways like PI3K-AKT and MAPK signaling pathways. It inhibits the secretion of inflammatory and angiogenic factors, inhibits endothelial angiogenesis, and plays a role in treating PSCI.