Current pharmaceutical design最新文献

Ursolic acid, a natural pentacyclic triterpenoid compound, has been shown to have significant cardioprotective effects in various preclinical studies. This article reviews the various mechanisms by which ursolic acid achieves its cardioprotective effects, highlighting its potent anti-oxidant, anti-inflammatory, and anti- apoptotic properties. Ursolic acid upregulates anti-oxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), effectively reducing oxidative stress, thereby decreasing reactive oxygen species (ROS) and improving lipid peroxidation levels. Furthermore, ursolic acid downregulates pro-inflammatory cytokines and inhibits key inflammatory pathways, such as nuclear factor kappa B (NF-κB), which results in its anti-inflammatory effects. These actions help in protecting cardiac tissues from acute and chronic inflammation. Ursolic acid also promotes mitochondrial function and energy metabolism by enhancing mitochondrial biogenesis and reducing dysfunction, which is critical during ischemia-reperfusion (I/R) injury. Additionally, ursolic acid influences multiple molecular pathways, including B-cell leukemia/lymphoma 2 protein (Bcl- 2)/Bcl-2 associated x-protein (Bax), miR-21/extracellular signal-regulated kinase (ERK), and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), to reduce cardiomyocyte apoptosis. Collectively, these properties make ursolic acid a promising therapeutic agent for cardiovascular diseases (CVDs), warranting further research and clinical trials to harness its potential fully.

Research on shape memory materials (SMM) or smart materials, along with advancements in printing technology, has transformed three-dimensional (3D) printing into what we now refer to as 4D printing. In this context, the addition of time as a fourth dimension enhances 3D printing. 4D printing involves the creation of 3D-printed objects that can change their shapes into complex geometries when influenced by external stimuli such as temperature, light, or pH over time. Currently, the use of smart materials in 4D printing is being explored extensively across various fields, including automotive, wearable electronics, soft robotics, food, mechatronics, textiles, biomedicine, and pharmaceuticals. A particular focus is on designing and fabricating smart drug delivery systems (DDS). This review discusses the evolution of 3D printing into 4D printing, highlighting the differences between the two. It covers the history and fundamentals of 4D printing, the integration of machine learning in 4D printing, and the types of materials used, such as stimuli-responsive materials (SRMs), hydrogels, liquid crystal elastomers, and active composites. Moreover, it presents various 4D printing techniques. Additionally, the review highlights several smart DDS that have been fabricated using 4D printing techniques. These include tablets, capsules, grippers, scaffolds, robots, hydrogels, microneedles, stents, bandages, dressings, and other devices aimed at esophageal retention, gastro-retention, and intravesical DDS. Lastly, it elucidates the current limitations and future directions of 4D printing.

Introduction: Dryopteris ramosa is a high-altitude plant of moist and shady habitat. Its aerial parts are edible and orally administered as an antibiotic and effective aphrodisiac. They are also used as pesticides, astringents, and febrifuges.

Aim: The present study aimed to elucidate the plant's medicinal potential as an anticancer agent. Extracts of Dryopteris ramosa were examined for cytotoxic effects against AGS, A549, and HCT116 cell lines. The project also aimed to evaluate the phytochemical constitutents of the plant. For this purpose, GC-ToF-MS analysis was executed to identify the bioactive compounds in the aerial parts extract of Dryopteris ramosa. As a result, 93 different phytochemicals were identified from the spectral properties of GC-ToF-MS which contain 19 compounds of high peaks having reported anti-inflammatory, Anti-diabetic, Antibacterial, Analgesic, and antioxidant potential.

Methods: Three different cell lines have been treated against Ethanol, Methanol, Ethyl acetate, Water, Chloroform, Acetone, and n-hexane extracts from the aerial parts of Dryopteris ramosa. These cell lines were checked and were ranked in lethality based on IC50 value. The extract samples were processed as serial dilution from high concentrations (500 ug/ml). All the three cell lines were treated for 48 hours.

Results: Extracts showed a significant effect in different cell lines (based on IC50 less than 200 ug/ml). Performing the in-vitro anticancer activity against the three different cell lines in Ethyl Acetate, Methanol, nhexane, Chloroform and Acetone extract of Dryopteris indicated that anticancer activity of the plant is high against AGS and A549 cell line while less prominent in HTC116 cell lines through MTT Assay. Insilico drug-likeness and ADMET analysis were studied of the compounds, that exhibit considerable drug likenesses, phytochemical medicinal chemistry, and a promising ADMET score and no toxicity. The candidate compounds were chosen for further elucidation by Molecular Docking and dynamic simulations. Employing the molecular docking approach for virtual screening of the phytochemicals it was found that the compounds Germacrene showed remarkable results towards BCL2 with -7Kcal/Mol and a-D-(+)-Xylopyranose showed significant docking results towards 5P21 with -7.1Kcal/Mol.

Conclusion: For multi-scale frames structural aberrations and fluctuations identification of the docked complexes, a molecular dynamics analysis was performed for a 100 ps simulation run by accessing the online tool of MDweb simulations. These molecular docking and simulation analyses also revealed that both the phytochemicals have a stable interaction with the cancer-related proteins BCL2 and 5P21.

Background: About 10-15% of all breast cancers comprise triple-negative breast cancer (TNBC), defined as cancer cells that lack receptors for the ER, PR, and HER2 protein receptors. Due to the absence of these receptors, treating TNBC using conventional chemotherapy is challenging and, therefore, requires the discovery of novel chemotherapeutic agents derived from natural sources.

Objective: The current work was intended to study the potential phytochemicals of Ajwa dates (Phoenix dactylifera L.) with the predicted potential targets (namely, Akt and PI3K) to determine possible TNBC inhibitors.

Methods: We harnessed network pharmacology, molecular docking, drug-likeness studies, Molecular Dynamics (MD) simulation, and binding free energy (MM-GBSA) calculation to get phytochemicals with potential effects against TNBC. Firstly, molecular docking was performed on 125 phytochemicals against the Akt and PI3K proteins utilizing PyRx. Then, the phytochemicals with the highest binding affinity (≤ -8.1 kcal/mol) were examined for in silico drug-likeness and toxicity profiles. Finally, phytochemicals with optimal druglikeness and toxicity profiles were studied by Molecular Dynamics (MD) simulation and binding free energy (MM-GBSA) to identify compounds that can form stable complexes.

Results: The results of the network pharmacology revealed that the Akt and PI3K proteins are potential targets of TNBC for the phytochemicals of Phoenix dactylifera L. used in this study. The outcomes of molecular docking displayed that among 125 phytochemicals, 42 of them (with a binding affinity ≤ -8.1 kcal/mol) have potentially inhibiting effects on both proteins PI3K and Akt expressed in TNBC. Then, the results of in silico drug-likeness identified seven phytochemicals with optimal pharmacokinetic profiles. Furthermore, toxicity studies showed that three phytochemicals (namely, Chrysoeriol, Daidzein, and Glycitein) did not cause any toxicities. Finally, the Molecular Dynamics (MD) simulation studies and binding free energy (MM-GBSA) verified that Daidzein stayed within the binding cavities of both proteins (Akt and PI3K) by establishing a stable protein-ligand complex during simulation.

Conclusion: Taken together, the current work emphasizes the potential effects of Daidzein from Phoenix dactylifera L. against TNBC, and it can be further studied to establish it as a standard chemotherapy for TNBC.

Background: Effective management strategies against tick infestations are necessary because tickborne diseases represent serious hazards to the health of humans and animals worldwide. The aim of this study was to examine the larvicidal and ovicidal properties of Xanthium strumarium extract against a notorious tick species, Rhipicephalus microplus.

Methodology: The maceration method was used to prepare the ethanolic extract of X. strumarium. The extract was then used in an adult immersion test (AIT) and larval packet test (LPT) to asses the plant's toxicity. To elucidate the mode of action, molecular modeling and docking studies were conducted. ADMET analysis was then carried out to find out the drug-likeness profiles of the plant phytochemicals.

Results: Significant death rates and egg inhibition were found at different extract doses using the larval packet test (LPT) and adult immersion test (AIT). A concentration-dependent impact was observed at a concentration of 40 mg/mL, which resulted in the maximum larval mortality (92 ± 2.646) and egg inhibition (77.057 ± 2.186). Additionally, the potency of the extract against R. microplus was determined by calculating its fatal concentrations (LC50, LC90, and LC99). A three-dimensional model of the R. microplus octopamine receptor was created, and docking studies showed that the receptor and possible ligands, most notably Xanthatin and Xanthosin, interacted well. The potential of compounds as tick control agents was highlighted by their pharmacokinetic characteristics and toxicity profiles, as revealed by drug-likeness and ADMET studies. Molecular dynamic simulations further demonstrated the stability of the protein-ligand complex, indicating the consistent association between the ligand and the target protein.

Conclusion: Overall, this study provides valuable insights into the potential use of X. strumarium extract and its compounds as larvicidal and ovicidal agents against R. microplus, paving the way for further research on tick control strategies.

Childhood overweight and obesity are nutritional disorders in which children's energy intake exceeds energy consumption for a long period, resulting in the excessive accumulation of body fat and weight that exceeds a certain range. It is one of the most serious public health issues. In recent years, its prevalence has shown a significant upward trend, and 41-80% of childhood obesity can persist into adulthood.Scholars are now more interested in researching this further. Since antibiotics have been used extensively since their discovery, more focus has been paid to the possible risks these medications pose to children who are exposed to them. Recently, some studies have explored the possible link between antibiotic exposure and the prevalence of overweight and obesity in children. However, their findings are inconsistent. Therefore, this review aims to synthesize and summarize the studies related to the effects of antibiotics on childhood obesity, elucidate the possible associations between the two, and provide an in-depth discussion of the potential biological mechanisms by which antibiotics exposure may contribute to childhood obesity.

Cordyceps spp. (CS), a well-known medicinal mushroom that belongs to Tibetan medicine and is predominantly found in the high altitudes in the Himalayas. CS is a rich reservoir of various bioactive substances including nucleosides, sterols flavonoids, peptides, and phenolic compounds. The bioactive compounds and CS extract have antibacterial, antioxidant, immunomodulatory, and inflammatory properties in addition to organ protection properties across a range of disease states. The study aimed to review the potential of CS, a medicinal mushroom, as a treatment for sepsis. While current sepsis drugs have side effects, CS shows promise due to its anti-inflammatory, antioxidant, and antibacterial properties. We have performed an extensive literature search based on published original and review articles in Scopus and PubMed. The keywords used were Cordyceps, sepsis, and inflammation. Studies indicate that CS extract and bioactive compounds target free radicals including oxidative as well as nitrosative stress, lower inflammation, and modulate the immune system, all of which are critical components in sepsis. The brain, liver, kidneys, lungs, and heart are among the organs that CS extracts may be able to shield against harm during sepsis. Traditional remedies with anti-inflammatory and protective qualities, such as Cordyceps mushrooms, are promising in sepsis. However, more research including clinical trials is required to validate the usefulness of CS metabolites in terms of organ protection and fight infections in sepsis.

Type 1 Diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells, leading to hyperglycemia and various complications. Despite insulin replacement therapy, there is a need for therapies targeting the underlying autoimmune response. This review aims to explore the mechanistic insights into T1D pathogenesis and the impact of delivery systems on immunotherapy. Genetic predisposition and environmental factors contribute to T1D development, triggering an immune-mediated attack on β-cells. T cells, particularly CD4+ and CD8+ T cells, play a central role in β-cell destruction. Antigen- specific immunotherapy is a unique way to modify the immune system by targeting specific antigens (substances that trigger the immune system) for immunotherapy. It aims to restore immune tolerance by targeting autoantigens associated with T1D. Nanoparticle-based delivery systems offer precise antigen delivery, promoting immune tolerance induction. Various studies have demonstrated the efficacy of nanoparticle-mediated delivery of autoantigens and immunomodulatory agents in preclinical models, and several patents have been made in T1D. Combining antigen-specific immunotherapy with β-cell regeneration strategies presents a promising approach for T1D treatment. However, challenges remain in optimizing delivery systems for targeted immune modulation while ensuring safety and efficacy.

Hepatotoxicity is a critical health hazard, primarily contributing to the increased incidence of deaths globally. The liver is one of the major and extremely vital organs of the human body. Autoimmune diseases, viruses, exposure to toxicants such as carcinogens, and changes in eating habits can all cause liver problems, among other things. Free radical generation, together with raised enzyme levels including SGOT, SGPT, and total bilirubin, are among the pathological changes set off by liver injury. Hepatotoxicity causes changes in cells, such as eosinophilic cytoplasm, nuclear pyknosis, fatty degeneration, too many liver lesions, and hepatic centrilobular necrosis due to lipid peroxidation. Researchers have used animal models to investigate liver diseases and toxicities. Drugs such as azathioprine, alcoholism, paracetamol intoxication, and anti-tuberculosis drugs are some of the most common causes of liver toxicity. These toxins cause calcium ions (Ca2+), reactive oxygen species (ROS), and inflammatory mediators to be released inside cells. This activates immune cells like NK cells, NKT cells, and Kupffer cells. These signaling pathways also play roles in hepatotoxicity. Due to its pathogenesis, no effective drug is currently available for hepatotoxicity due to a lack of understanding related to the signaling factors involved in it. The paper primarily examines different experimental models of hepatotoxicity, including non-invasive and invasive methods, as well as genetic models. As such, these models are crucial tools in advancing our understanding of hepatotoxicity, thus paving the way for new therapeutic interventions.

Introduction: Non-Small-Cell Lung Cancer (NSCLC) represents the leading cause of cancer deaths in the world. We previously found that daidzein, one of the key bioactivators in soy isoflavone, can inhibit NSCLC cell proliferation and migration, while the molecular mechanisms of daidzein in NSCLC remain unclear.

Methods: We developed an NSCLC nude mouse model using H1299 cells and treated the mice with daidzein (30 mg/kg/day). Mass spectrometry analysis of tumor tissues from daidzein-treated mice identified 601 differentially expressed proteins (DEPs) compared to the vehicle-treated group. Gene enrichment analysis revealed that these DEPs were primarily associated with immune regulatory functions, including B cell receptor and chemokine pathways, as well as natural killer cell-mediated cytotoxicity. Notably, the NOD-like receptor signaling pathway, which is closely linked to pyroptosis, was significantly enriched.

Results: Further analysis of key pyroptosis-related molecules, such as ASC, CASP1, GSDMD, and IL-1β, revealed differential expression in NSCLC versus normal tissues. High levels of ASC and CASP1 were associated with a favorable prognosis in NSCLC, suggesting that they may be critical effectors of daidzein's action. In NSCLC-bearing mice treated with daidzein, RT-qPCR and Western blot analyses showed elevated mRNA and protein levels of ASC, CASP1, and IL-1β but not GSDMD, which was consistent with the proteomic data.

Conclusion: In summary, this study demonstrated that daidzein inhibits NSCLC growth by inducing pyroptosis. Key pathway modulators ASC, CASP1, and IL-1β were identified as primary targets of daidzein. These findings offer insights into the molecular mechanisms underlying the anti-NSCLC effects of daidzein and could offer dietary recommendations for managing NSCLC.