Drug Target Insights最新文献

Background: Edible fruits and resins provide various benefits to mankind including potential medicinal applications. This study aimed to determine the cytotoxicity, selectivity, and clonogenicity of fruits and exudates of certain Saudi medicinal plants (Anethum graveolens (BEP-09), Opuntia ficus-indica (L.) Miller (BEP-10), Boswellia serrata Roxb. ex Colebr. (BEP-11), and Commiphora myrrha (BEP-12)) against human liver adenocarcinoma (HepG2).

Methods: Initial cytotoxicity and cell line selectivity against different cell lines were screened using MTT assay. The most promising extract was subjected to gas chromatography-mass spectrometry (GC-MS) analysis to determine the main phytoconstituents. Clonogenicity was checked for the most active extract.

Results: The selected plants' fruits and resins possess a significant cytotoxic activity estimated as IC₅₀. The fruit of BEP-10 was found to be the most active extract against liver cancer cells (IC₅₀ = 2.82) comparable to both doxorubicin (IC₅₀ = 1.40) and camptothecin (IC₅₀ = 1.11). It showed a selectivity index of 4.47 compared to the normal human foetal lung fibroblast (MRC5) cells. BEP-10 showed a dose-dependent clonogenic effect against HepG2 cells comparable to the effect of doxorubicin. The GC-MS chromatogram of BEP-10 extract revealed the presence of eight small polar molecules, representing 73% of the total identified compounds and the rest three molecules (27%) were non-polar constituents. The furan derivatives represent the chief components in BEP-10 (16.3%), while the aldehyde 5-(hydroxymethyl)-2-furancarboxaldehyde was found to be the main molecule (13.2%).

Conclusion: The fruits of BEP-10 have a potential cytotoxic effect particularly against HepG2. The identified phytoconstituents in the tested plant extract might contribute to the investigated cytotoxic activity.

Background: Levofloxacin, a fluoroquinolone, is an extensively used antibiotic effective against both positively and negatively staining bacteria. It works by inhibiting bacterial topoisomerase type II and topoisomerase type IV, resulting in impaired DNA synthesis and bacterial cell death. Eryptosis is another term for apoptotic cell death of erythrocyte marked by cell shrinkage, phosphatidylserine (PS) flipping, and membrane blebbing.

Methods: The intent of the present research was to look at the eryptotic effect of levofloxacin by exposing erythrocytes to therapeutical doses (7, 14 µM) of levofloxacin for 48 hours. Cell size evaluation, PS subjection to outside, and calcium channel inhibition were carried out to investigate eryptosis. Oxidative stress generated by levofloxacin was measured as a putative mechanism of eryptosis using glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase activities. Similarly, hemolysis measurements demonstrated levofloxacin's cytotoxic effect.

Results: Our findings showed that therapeutic doses of levofloxacin can cause a considerable decline in antioxidant enzymes activities, as well as induce cell shrinkage, PS externalization, and hemolysis in erythrocytes. The role of calcium in triggering erythrocyte shrinkage was also confirmed.

Conclusion: In conclusion, our findings showed that the indicated levofloxacin doses caused oxidative stress, which leads to erythrocyte death via eryptosis and hemolysis. These findings emphasize the importance of using levofloxacin with caution and the need for additional research to mitigate these side effects.

Objective: Cancer or neoplasm is a cosmopolitan catastrophe that results in more than 20 million new cases and 10 million deaths every year. Some factors lead to carcinogenesis like infectious diseases. Parasites like Toxoplasma gondii, by its components, could modulate the cancer system by inducing apoptosis. The objective of this investigation is to assess the potential of peptides derived from T. gondii in combating cancer by examining their effects on Caco-2, Hep-G2, and HT29 cell lines.

Materials and methods: Candidate peptide by its similarity to anticancer compounds was predicted through the computer-based analysis/platform. The impact of the peptide on cell viability, cell proliferation, and gene expression was evaluated through the utilization of MTT assay, flow cytometry, and real-time polymerase chain reaction (PCR) methodologies.

Results: The cell viability rate exhibited a significant decrease (p < 0.001) across all cell lines when exposed to a concentration of ≤160 μg. Within the 48-hour timeframe, the half maximal inhibitory concentration (IC₅₀) for HT29 and Hep-G2 cell lines was determined to be 107.2 and 140.6 μg/mL, respectively. Notably, a marked decrease in the expression levels of Bcl2 and APAF1 genes was observed in both the Hep-G2 and HT29 cell lines.

Conclusion: These findings indicate that the T. gondii peptide affected cancer cell mortality and led to changes in the expression of genes associated with apoptosis.

Objective: Anti-pathogenic potential of a polyherbal formulation Enteropan® was investigated against a multidrug-resistant strain of the bacterium Pseudomonas aeruginosa.

Methods: Growth, pigment production, antibiotic susceptibility, etc., were assessed through appropriate in vitro assays. Virulence of the test pathogen was assessed employing the nematode worm Caenorhabditis elegans as a model host. Molecular mechanisms underlining the anti-pathogenic activity of the test formulation were elucidated through whole transcriptome analysis of the extract-exposed bacterial culture.

Results: Enteropan-pre-exposed P. aeruginosa displayed reduced (~70%↓) virulence towards the model host C. elegans. Enteropan affected various traits like biofilm formation, protein synthesis and secretion, quorum-modulated pigment production, antibiotic susceptibility, nitrogen metabolism, etc., in this pathogen. P. aeruginosa could not develop complete resistance to the virulence-attenuating activity of Enteropan even after repeated exposure to this polyherbal formulation. Whole transcriptome analysis showed 17% of P. aeruginosa genome to get differentially expressed under influence of Enteropan. Major mechanisms through which Enteropan exerted its anti-virulence activity were found to be generation of nitrosative stress, oxidative stress, envelop stress, quorum modulation, disturbance of protein homeostasis and metal homeostasis. Network analysis of the differently expressed genes resulted in identification of 10 proteins with high network centrality as potential targets from among the downregulated genes. Differential expression of genes coding for five (rpoA, tig, rpsB, rpsL, and rpsJ) of these targets was validated through real-time polymerase chain reaction too, and they can further be pursued as potential targets by various drug discovery programmes.

Background: Pistacia chinensis is extensively employed in traditional medicine. This study aimed to isolate and evaluate the therapeutic effects of 3'4'78-tetrahydroxy-3-methoxyflavone from P. chinensis crude extract.

Materials and methods: The study utilized column chromatography for isolation. The plant extract and its isolated compound were assessed for in vivo analgesic (hot plate model), anti-inflammatory (carrageenan-induced paw edema), sedative (open field model), and muscle relaxing properties (inclined plane and traction test).

Results: In the thermal-induced analgesic model, a significant analgesic effect was observed for the extract (25, 50, and 100 mg/kg) and the isolated compound (2.5, 5, 10, and 15 mg/kg) at higher doses. The extract (100 mg/kg) significantly prolonged latency time (21.98 seconds) after 120 minutes of administration. The isolated compound elevated the latency time (20.03 seconds) after 30 minutes, remaining significant up to 120 minutes with a latency time of 24.11 seconds. The anti-inflammatory effect showed a reduction in inflammatory reactions by 50.23% (extract) and 67.09% (compound) after the fifth hour of treatment. Both samples demonstrated significant sedative effects, with the extract hindering movement by 54.11 lines crossed compared to the negative control (180.99 lines). The isolated compound reduced the number of lines crossed to 15.23±SEM compared to the negative control. Both samples were also significant muscle relaxants. Docking studies indicated that the compound's therapeutic effect is due to inhibiting COX and nociceptive pathways.

Conclusion: The isolated compound from Pistacia chinensis exhibits significant analgesic, anti-inflammatory, sedative, and muscle relaxing properties, with potential therapeutic applications by inhibiting COX and nociceptive pathways.

Aim: Researchers using herbs and natural products to find new drugs often prefer flavonoids because of their potential as antioxidants and anti-inflammatories. The planned review addressed baicalein research findings in detail. This manuscript provides a complete review of baicalein's potential pharmacological effects along with several molecular targets for better understanding of its therapeutic activities.

Materials and methods: We targeted the review on in vitro and in vivo studies reported on baicalein. For this, the literature is gathered from the database available on search engines like PubMed, ScienceDirect, Scopus, and Google Scholar up to 21 December 2023. The keywords "Scutellaria baicalensis", "Oroxylum indicum", "Neuroprotective", "Cardioprotective", "Toxicity studies", and "Baicalein" were used to fetch the content.

Results: Baicalein's molecular receptor binding approach has shown anticancer, antidiabetic, antimicrobial, antiaging, neuroprotective, cardioprotective, respiratory protective, gastroprotective, hepatic protective, and renal protective effects. The synergistic effects of this drug with other selective herbs are also contributed towards significant therapeutic potential.

Conclusion: This systematic review article from a contemporary and scientific perspective offers fresh insight into S. baicalensis, O. indicum, and its bioactive component baicalein as a potential complementary medicine. Baicalein may be transformed into more efficacious and acceptable evidence-based medicine. However, we recommend more clinical and mechanistic approaches to confirm safety and efficacy of baicalein.

Introduction: It is unclear whether induced spike protein-specific antibodies due to infections with SARS-CoV-2 or to the prototypic Wuhan isolate-based vaccination can immune-react with the emerging variants of SARS-CoV-2.

Aim/objectives: The main objective of the study was to measure the immunoreactivity of induced antibodies postvaccination with Covishield™ (ChAdOx1 nCoV-19 coronavirus vaccines) or infections with SARS-CoV-2 by using selected peptides of the spike protein of wild type and variants of SARS-CoV-2.

Methodology: Thirty patients who had recovered from SARS-CoV-2 infections and 30 individuals vaccinated with both doses of Covishield™ were recruited for the study. Venous blood samples (5 mL) were collected at a single time point from patients within 3-4 weeks of recovery from SARS-CoV-2 infections or receiving both doses of Covishield™ vaccines. The serum levels of total immunoglobulin were measured in both study groups. A total of 12 peptides of 10 to 24 amino acids length spanning to the receptor-binding domain (RBD) of wild type of SARS-CoV-2 and their variants were synthesized. The serum levels of immune-reactive antibodies were measured using these peptides.

Results: The serum levels of total antibodies were found to be significantly (p<0.001) higher in the vaccinated individuals as compared to COVID-19 recovered patients. Our study reported that the mutations in the RBD at the residues K417, E484, and N501 have been associated with reduced immunoreactivity with anti-sera of vaccinated people and COVID-19 recovered patients.

Conclusion: The amino acid substitutions at the RBD of SARS-CoV-2 have been associated with a higher potential to escape the humoral immune response.

Drug repurposing is a strategic endeavor that entails the identification of novel therapeutic applications for pharmaceuticals that are already available in the market. Despite the advantageous nature of implementing this particular strategy owing to its cost-effectiveness and efficiency in reducing the time required for the drug discovery process, it is essential to bear in mind that there are various factors that must be meticulously considered and taken into account. Up to this point, there has been a noticeable absence of comprehensive analyses that shed light on the limitations of repurposing drugs. The primary aim of this review is to conduct a thorough illustration of the various challenges that arise when contemplating drug repurposing from a clinical perspective in three major fields-cardiovascular, cancer, and diabetes-and to further underscore the potential risks associated with the emergence of antimicrobial resistance (AMR) when employing repurposed antibiotics for the treatment of noninfectious and infectious diseases. The process of developing repurposed medications necessitates the application of creativity and innovation in designing the development program, as the body of evidence may differ for each specific case. In order to effectively repurpose drugs, it is crucial to consider the clinical implications and potential drawbacks that may arise during this process. By comprehensively analyzing these challenges, we can attain a deeper comprehension of the intricacies involved in drug repurposing, which will ultimately lead to the development of more efficacious and safe therapeutic approaches.

Immunotherapy has become an integral part of a comprehensive treatment approach to metastatic colorectal cancer (mCRC). Nivolumab (Opdivo) is a human immunoglobulin G4 monoclonal antibody that blocks the interaction between the programmed cell death 1 (PD-1) receptor and its ligands 1/2 (PD-L1/PD-L2), leading to inhibition of T-cell proliferation, cytokine secretion, and enhanced immune response. The US Food and Drug Administration (FDA) has approved this drug for use in high microsatellite instability (MSI-high)/deficiencies in mismatch repair (dMMR) advanced CRC patients. However, its efficacy is extremely limited in microsatellite stability (MSS)/mismatch repair proficient (pMMR) patients. We report a case of a 42-year-old man diagnosed with MSS/pMMR mCRC who has achieved a durable response to nivolumab after a progression under chemotherapy with antiangiogenic treatment. We observed for the first time an atypical response after 8 months of nivolumab treatment, with the regression of previous primary pulmonary lesions and the presence of new para-aortic lymph node lesions. This report demonstrates that a subset of pretreated mCRC patients with the MSS/pMMR phenotype may benefit from nivolumab and these patients need more attention.