Current pharmaceutical biotechnology最新文献

Background: Leishmaniasis is responsible for approximately 65,000 annual deaths. Various Leishmania species are the predominant cause of visceral, cutaneous, or mucocutaneous leishmaniasis, affecting millions worldwide. The lack of a vaccine, emergence of resistance, and undesirable side effects caused by antileishmanial medications have prompted researchers to look for novel therapeutic approaches to treat this disease. Antimicrobial peptides (AMPs) offer an alternative for promoting the discovery of new drugs.

Methods: In this study, we detail the synthesis process and investigate the antileishmanial activity against Leishmania (Viannia) braziliensis for peptides belonging to the dermaseptin (DS) family and their synthetic analogs. The MTT assay was performed to investigate the cytotoxicity of these peptides on the murine macrophage cell line RAW 264.7. Subsequently, we performed molecular modeling analysis to explore the structure-function correlation of the derivatives interacting with the parasitic membrane.

Results: All examined derivatives displayed concentration-dependent antileishmanial effect at low concentrations. Their effectiveness varied according to the peptide's proprieties. Notably, peptides with higher levels of charge demonstrated the most pronounced activities. Cytotoxicity assays showed that all the tested peptides were not cytotoxic compared to the tested conventional drug. The structure-function relationships demonstrated that the charged N-terminus could be responsible for the antileishmanial effect observed on promastigotes.

Conclusion: Collectively, these results propose that dermaseptins (DS) might offer potential as promising candidates for the development of effective antileishmanial therapies.

Introduction: Honey possesses several positive properties, making it effective in wound healing mechanisms. However, very little information is available on the different honey types for wound healing activity.

Method: In the first "Academy of Sciences", a public engagement project with high school students, we assessed the properties of thirteen kinds of honey from the Piedmont area (Nord West Italy). In particular, we characterized the color intensity (by Pfund scale), total phenolic content (TPC), total flavonoid content (TFC), H²O² production, and wound closure rate.

Results: Then, we tried to verify the presence of a correlation between these parameters, finding a positive correlation between H²O² and wound closure rate.

Conclusion: These data pave the way to characterize different types of Italian honey to completely understand its potential.

Introduction: Doxorubicin (DOX) is one of the most potent anticancer drugs that has ubiquitous usage in oncology; however, its marked adverse effects, such as cardiotoxicity, are still a major clinical issue. Plant extracts have shown cardioprotective effects and reduced the risk of cardiovascular diseases.

Method: The current study is intended to explore the cardioprotective effect of ethanolic Moringa Oleifera extracts (MOE) leaves loaded into niosomes (MOE-NIO) against DOXinduced cardiotoxicity in rats. MOE niosomes nanoparticles (NIO-NPs) were prepared and characterized by TEM. Seventy male Wistar rats were randomly divided into seven groups: control, NIO, DOX, DOX+MOE, DOX+MOE-NIO, MOE+DOX, and MOE-NIO+DOX. DOX (4 mg/kg, IP) was injected once per week for 4 weeks with daily administration of MOE or MOENIO (250 mg/kg, PO) for 4 weeks; in the sixth and seventh groups, MOE or MOE-NIO (250 mg/kg, PO) was administered one week before DOX injection. Various parameters were assessed in serum and cardiac tissue. Pre and co-treatment with MOE-NIO have mitigated the cardiotoxicity induced by DOX as indicated by serum aspartate aminotransferase (AST), creatine kinase - MB(CK-MB) and lactate dehydrogenase (LDH), cardiac Troponin 1(cTn1) and lipid profile. MOE-NIO also alleviated lipid peroxidation (MDA), nitrosative status (NO), and inflammatory markers levels; myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-α) obtained in DOX-treated animals. Additionally, ameliorated effects have been recorded in glutathione content and superoxide dismutase activity. MOE-NIO effectively neutralized the DOXupregulated nuclear factor kappa B (NF-kB) and p38 mitogen-activated protein kinases (p38 MAPK), and DOX-downregulated nuclear factor-erythroid 2-related factor 2 (Nrf2) expressions in the heart.

Results: It is concluded that pre and co-treatment with MOE-NIO could protect the heart against DOX-induced cardiotoxicity by suppressing numerous pathways including oxidative stress, inflammation, and apoptosis and by the elevation of tissue antioxidant status.

Conclusion: Thus, it may be reasonable to suggest that pre and co-treatment with MOE-NIO can provide a potential cardioprotective effect when doxorubicin is used in the management of carcinoma.

Introduction: Non-small cell lung cancer (NSCLC) is a type of malignant tumor with high morbidity as well as mortality. The process of lung cancer may be driven by cancer stem cells. It was known that MFAP5 enhanced the occurrence of diverse types of cancer. Also, MFAP5 has the potential to induce the degradation of FBW7 which is a tumor suppressor. Lower levels of FBW7 enhance the stability of Sox9, which is the cancer stem cell-related protein. However, whether the MFAP5 can modulate the stem cell features of NSCLC cells by modulating the FBW7/Sox9 axis is unclear. Therefore, this study aimed to explore the role of MFAP5/FBW7/Sox9 axis on the stem cell features of NSCLC cells and develop a new treatment of this carcinoma.

Material and methods: In this study, we explored the effects of MFAP5 on the stem cell features of NSCLC cells for the first time. We established MFAP5 overexpression and knockdown NSCLC cells. Clone formation assays and cell sphere culture assays were conducted for the exploration of the growth and stem cell features of these cells. Western blotting was applied for the detection of Sox9 and FBW7 expression in these cells. CHX was applied for the treatment of these cells for the detection of degradation of Sox9. Finally, we overexpressed the Sox9 in MFAP5 knockdown NSCLC cells.

Results: MFAP5 promoted the growth and stem cell features of these cells. Knockdown of MFAP5 induced higher levels of FBW7 while restricting the expression of Sox9. Knockdown of MFAP5 aggravated the degradation of Sox9. Overexpression of Sox9 abrogated the efficacy of MFAP5 inhibition on the growth as well as stem cell features of these cells. The results of this study clarified the role of MFAP5/FBW7/Sox9 axis on the development of non-small cell lung cancer cells, providing the potential therapeutic target for the clinical treatment of NSCLC.

Conclusion: MFAP5 maintained the stem cell features of non-small cell lung cancer cells by modulating FBW7/Sox9 axis.

In the last few decades, the rates of infertility among women have been on the rise, usually due to complications with the uterus and related tissue. A wide variety of reasons can cause uterine factor infertility and can be congenital or a result of disease. Uterine transplantation is currently used as a means to enable women with fertility issues to have a natural birth. However, multiple risk factors are involved in uterine transplantation that threaten the lives of the growing fetus and the mother, as a result of which the procedure is not prominently practiced. Uterine tissue engineering provides a potential solution to infertility through the regeneration of replacement of damaged tissue, thus allowing healing and restoration of reproductive capacity. It involves the use of stem cells from the patient incorporated within biocompatible scaffolds to regenerate the entire tissue. This manuscript discusses the need for uterine tissue engineering, giving an overview of the biological and organic material involved in the process. There are numerous existing animal models in which this procedure has been actualized, and the observations from them have been compiled here. These models are used to develop a further understanding of the integration of engineered tissues and the scope of tissue engineering as a treatment for uterine disorders. Additionally, this paper examines the scope and limitations of the procedure.

The world's one of the major causes of death are cancer. Cancer is still a complex disease over the years that needs to be cured. Traditional cytotoxic approaches, although they have been implemented for years for treating neoplastic diseases, yet are limited due to the intricacy and low efficiency of cancer cells. Researchers are thus compelled to seek more potent therapeutic strategies. Chimeric antigen receptor (CAR-T) cell therapy is one such innovative insight where T lymphocytes are altered genetically to target cancer cells. Despite the outstanding accomplishment in patients with haematological malignancies, CAR-T cell treatment has demonstrated minimal impact on solid tumours due to a number of obstacles, including proliferation, stability, trafficking, and fate within tumors. Furthermore, interactions between the host and tumour microenvironment with CAR-T cells significantly alter CAR-T cell activities. Designing and implementing these treatments additionally also requires a complex workforce. Overcoming these significant challenges, there is a requirement for innovative strategies for developing CAR-T cells with greater anti-tumour efficacy and reduced toxicity. In this chapter, the current advancement in CAR-T cell technology in order to increase clinical efficacy in both solid tumors and haematological, as well as possibilities to conquer the limits of CAR-T cell therapy in both solid and haematological tumours has been discussed.

Background: Tankyrases (TNKS) are homomultimers existing in two forms, viz. TNKS1 and TNKS2. TNKS2 plays a pivotal role in carcinogenesis by activating the Wnt//β- catenin pathway. TNKS2 has been identified as a suitable target in oncology due to its crucial role in mediating tumour progression. The discovery of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl) phenyl]imidazolidine-2,4-dione, a hydantoin phenylquinazolinone derivative which exists as a racemic mixture and in its pure enantiomer forms, has reportedly exhibited inhibitory potency towards TNKS2. However, the molecular events surrounding its chirality towards TNKS2 remain unresolved.

Methods: Herein, we employed in silico methods such as molecular dynamics simulation coupled with binding free energy estimations to explore the mechanistic activity of the racemic inhibitor and its enantiomer forms on TNKS2 at a molecular level.

Results: Favourable binding free energies were noted for all three ligands propelled by electrostatic and van der Waals forces. The positive enantiomer demonstrated the highest total binding free energy (-38.15 kcal/mol), exhibiting a more potent binding affinity to TNKS2. Amino acids PHE1035, ALA1038, and HIS1048; PHE1035, HIS1048 and ILE1039; and TYR1060, SER1033 and ILE1059 were identified as key drivers of TNKS2 inhibition for all three inhibitors, characterized by the contribution of highest residual energies and the formation of crucial high-affinity interactions with the bound inhibitors. Further assessment of chirality by the inhibitors revealed a stabilizing effect of the complex systems of all three inhibitors on the TNKS2 structure. Concerning flexibility and mobility, the racemic inhibitor and negative enantiomer revealed a more rigid structure when bound to TNKS2, which could potentiate biological activity interference. The positive enantiomer, however, displayed much more elasticity and flexibility when bound to TNKS2.

Conclusion: Overall, 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione and its derivatives showed their inhibitory prowess when bound to the TNKS2 target via in silico assessment. Thus, results from this study offer insight into chirality and the possibility of adjustments of the enantiomer ratio to promote greater inhibitory results. These results could also offer insight into lead optimization to enhance inhibitory effects.

Background: Breast Cancer (BRCA) is one of the most common cancers worldwide. Abnormal Alternative Splicing (AS) is frequently observed in cancers. Understanding the intricate relationship between gene mutations and abnormal AS is vital for developing novel diagnostic and therapeutic strategies to effectively target cancer.

Objective: This study aimed to focus on the analysis of transcriptomic splicing events in patients with Breast Cancer (BRCA), particularly those with mutations in the TP53 gene. Understanding the role of AS may be helpful in revealing potential predictive indicators for survival and treatment strategies.

Methods: The splicing data were downloaded from the Cancer Genome Atlas (TCGA) breast cancer project, incorporating 972 patients in the study, classified according to TP53 mutation status. A comprehensive splicing profile of these breast tumors was outlined, and an interaction network of Alternative Splicing (AS) events and splicing factors was constructed. This allowed for the identification of specific AS events associated with TP53-mutant breast cancer. A prognostic risk model based on AS events was established, using univariate and multivariate Cox regression analyses. To understand the molecular heterogeneity, consensus clustering analyses of prognostic AS events were performed. We also investigated the association of AS patterns with the immune microenvironment and drug sensitivity.

Results: A total of 4519 significant Alternative Splicing (AS) events were distributed among 2729 genes that were altered in TP53 mutant tumors. Based on the analysis of these events, a prognostic risk model was created involving ten AS events from ten genes (such as NKTR, CD46, VCAN, etc.). The survival analysis showed that patients with high-risk scores had significantly poorer overall survival (p<0.001, HR=2.46, 95% CI 1.90-3.18) than those with low-risk scores. Furthermore, the study identified four molecular subtypes related to AS events (C1, C2, C3, and C4), which showed significant differences in immune cell infiltration, with C1 and C4 clusters having a higher degree of immune cell infiltration than C2 and C3. The chemosensitivity analysis revealed that these different AS clusters have different sensitivities to several anticancer drugs, such as docetaxel, paclitaxel, and doxorubicin, with C1 and C4 clusters being more sensitive than the other clusters.

Conclusion: We have demonstrated differential transcriptomic splicing events between TP53 mutant and wild-type cases of breast cancer, establishing an effective prognostic risk model based on AS events. These findings provide new insights that may aid in understanding the biological behavior of breast cancer and potentially in optimizing treatment strategies for breast cancer.

Introduction: A stone is a compact mass of one or more crystallised substances. The essential mechanism of stone formation is an excessive concentration of poorly soluble compounds in the urine. In excessive concentration, these compounds precipitate into crystals, which then aggregate to form a stone. The use of certain plants using the turbidimetric model has shown positive results on oxalocalcic crystallisation and, according to a recent study, has revealed very high inhibition rates.

Aim: The aim of this study was to dissolve calcium oxalate urinary stones using two medicinal plants with high inhibition rates by monitoring Ca2+ release, pH variation, and mass loss. The study consisted of treating the stones with two plants, Ficus-carica and Zea mays, at two concentrations of 10g/l and 25g/l for 24 hours.

Method: The main analytical techniques used in this study were as follows: Morphological analysis using a binocular magnifying glass, Fourier transform infrared spectroscopic method, and potentiometric method along with specific calcium electrode and an analytical balance. The study on the release of Ca2+ in the presence of the different herbal teas during 8 treatments of 3 to 4 hours was carried out on a series of 33 stones with the same chemical composition from several spontaneous expulsions of a 43-year-old male subject with lithiasis.

Results: The results showed a very remarkable effect of the Ficus-carica plant on Ca2+ release, which recorded 156.98 ppm, while Zea mays gave 130.63 ppm.

Conclusion: The kinetics of Ca2+ release were monitored by a potentiometer using a Ca2+- specific electrode. Zea mays at 10g/l showed a slightly positive effect on calculus dissolution compared to Ficus-carica.

Background: Gold nanoparticles (GNPs) have garnered significant attention in the biomedicine field due to their exceptional electrical, mechanical, chemical, and optical characteristics. The interaction of these remarkable potentials with biological tissues carries a risk of toxicity. Quercetin (Qur) is a natural flavonoid and exhibits numerous pharmacological impacts, especially anti-inflammatory, anti-apoptotic, and antioxidant.

Objective: This investigation aimed to clarify the potential cardiotoxicity induced by different diameters of spherical GNPs as well as to evaluate the possible cardioprotective roles of Qur against the most toxic diameter of GNPs.

Methods: Rats were randomly grouped and treated with or without sphere GNPs (10, 20 and 50 nm) and Qur (200 mg/kg b.wt.). Heart and blood samples were collected and subjected to histological, immunohistochemical and biochemical investigations.

Results: When compared to the groups treated with 20 and 50 nm, the 10 nm GNPs dramatically increased the levels of cardiac biomarkers, including Troponin I, Creatine kinase isoenzyme-MB (CK-MB), CK-Total, lactate dehydrogenase (LDH). Histopathologically, 10 nm GNPs exhibited severe cardiomyocytes degenerations, atrophy, disorganization of myocardial fibers, focal hemorrhage, congested blood vessels and interstitial inflammatory cells infiltrations. Immunohistochemically, 10 nm GNPs exhibited strongly positive expressions against anti-caspase-3 antibody confirming extensive apoptosis of cardiomyocytes. However, the majority of these pathological changes were significantly improved upon Qur treatment.

Conclusion: The size of GNPs is crucial to their toxicological impact on cardiac tissues where 10 nm GNPs can induce severe histological damage, potent cytotoxicity, and apoptosis rather than larger particles. Otherwise, pre-co-treatment with Qur revealed a significant cardioprotective effect against GNPs cardiotoxicity.