Current pharmaceutical design最新文献

Diabetic Neuropathy (DN) is a widespread and severely debilitating consequence of diabetes mellitus that impairs function, causes discomfort, and damages peripheral nerves. Numerous molecular pathways are involved in the pathogenesis of DN, including cyclooxygenase, polyol, protein kinase C, and inflammatory pathways. These molecular pathways may be responsible for the mechanism behind the onset and development of DN. The metabolic profile can be evaluated by examining the molecular mechanisms that connect diabetes to certain biochemical indicators. Historically, the use of plants and herbs as medicine has been highly valued in many populations. These traditional sources, either alone or in combination with contemporary drugs, are being studied by modern medicine for their potential applications in managing and treating diabetic neuropathy. The efficacy and potential negative effects of an herb are largely dependent on its purity and provenance. Rich supplies of bioactive chemicals with particular pharmacological qualities that don't have negative side effects can be found in many plants. Some phytoconstituents with antidiabetic properties are found in medicinal plants, including terpenoids, saponins, flavonoids or carotenoids, alkaloids, and glycosides. We conclude with the statement that developing novel therapeutic procedures for the therapy of DN would be aided by the effective manipulation of common molecular pathways.

Chitosan is a kind of natural material with many unique physicochemical and biological properties related to antibacterial, antioxidant, and chelating. In recent years, chitosan-based nano gels (CS-NG) have been widely used in the field of cancer nanomedicine due to their excellent characteristics including biodegradability, biocompatibility, flexibility, large surface area, controllability, high loading capacity, and especially it can be engineered to become stimuli-responsive to tumor environments. In this review, we summarized the main synthesis approaches of CS-NGs including radical polymerization, self-assembly, microemulsion, and ionic gelation methods. These novel CS-NGs are applied in cancer nanomedicine serving as drug delivery, gene delivery, and bioimaging. Besides, we proposed our perspectives regarding the clinical development of CS-NGs cancer nanomedicine applications.

Introduction: Sepsis, like neutropenic sepsis, is a medical condition in which our body overreacts to infectious agents. It is associated with damage to normal tissues and organs by the immune system, which leads to the spread of inflammation throughout our body. Of note, microRNAs (miRNAs) have been found to have a critical role in the sepsis progression. Such miRNAs are registered in the miRNA databases, such as Gene Expression Omnibus (GEO), with a specific identifier and unique characteristics. There is also computational software, such as TargetScan, that are broadly employed for the analysis of miRNAs, including their identification, target prediction, and functional analysis.

Methods: The current In-silico study aimed to predict miRNAs involved in sepsis progression. To this end, the GEO database was employed to find the sepsis-related genome profile. Afterward, down-regulated genes were selected for further bioinformatics analysis with the assumption that their decreased expression is associated with an increased sepsis progression. The miRNAs complementary to the selected genes were then predicted using TargetScan software. Based on the current In-silico analysis, seven miRNAs, including hsa-miR-325-3p, hsa-miR-146a-3p, hsa-miR-126-5p, hsa-miR-22-3p, hsa-miR-223-3p, hsa-miR-145-5p, and has-miR-181 family, were predicted to participate in sepsis pathogenesis. Among the predicted miRNAs, hsa-miR-325-3p has not been previously predicted or validated to be involved in septic conditions.

Results: Our prediction results showed that hsa-miR-325-3p may target genes implicating in both anti- (ETFB gene) and pro-inflammatory (TCEA1 and PTPN1 genes) responses, suggesting it is an immune hemostasis regulator during sepsis inflammation. Although the role of other predicted miRNAs has been already validated in the sepsis pathogenesis, the current study predicted new targets of these miRNAs, which have not been reported by previous In-silico or experimental studies on sepsis and other pathogenic conditions. Notably, other miRNAs, including hsa-miR-146a-3p, hsa-miR-126-5p, hsa-miR-22-3p, hsa-miR-223-3p, and hsa-miR-145-5p were predicted to target genes participating in inflammatory responses, including BLOC1S1, POLR2G, PTPN1, TCEA1, and CCT3.

Conclusion: In conclusion, the results of the present study can provide promising targets as therapeutic and diagnostic tools to treat and manage inflammation sepsis, such as neutropenic sepsis. However, these findings should be further evaluated in experimental studies to find their exact effects and underlying mechanisms.

Background: Psychosis, marked by detachment from reality, includes symptoms like hallucinations and delusions. Traditional herbal remedies like kratom are gaining attention for psychiatric conditions. This was aimed at comprehending the molecular mechanisms of Kratom's antipsychotic effects utilizing a multi-modal computational approach.

Materials and methods: This study employed network pharmacology followed by molecular docking and molecular dynamics simulation study to investigate the potential antipsychotic properties of kratom compounds by identifying their key molecular targets and interactions.

Results: Compounds present in kratom interact with a variety of receptors and proteins that play a pivotal role in neurotransmission, neurodevelopment, and cellular signaling. These interactions, particularly with dopamine and serotonin receptors, various proteins, and pathways, suggest a complex influence on psychiatric conditions. Both mitragynine and zotepine (an atypical antipsychotic drug) display significant binding affinities for 5HTR2A receptors, suggesting their potential for modulating related physiological pathways. Mitragynine displayed higher flexibility in binding compared to zotepine, which showed a more stable interaction. Hydrogen bond analysis revealed a more variable interaction profile for mitragynine than zotepine.

Conclusion: The research findings suggest that the interaction between kratom compounds and essential brain receptors could influence psychiatric conditions. Notably, both mitragynine (a key kratom component) and zotepine (an antipsychotic) bind to the 5HTR2A receptor, suggesting the potential for kratom to modulate similar pathways. Interestingly, mitragynine's flexible binding mode compared to zotepine might indicate a more diverse range of effects. Overall, the findings suggest complex interactions between kratom and the brain's signaling system, warranting further investigation into its potential therapeutic effects.

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.