Current pharmaceutical biotechnology最新文献

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.

Background: Inflammatory Bowel Disease (IBD) represents a chronic and recurrent inflammatory condition affecting the gastrointestinal tract, with a rising global incidence. Current treatment approaches include surgery and drugs. However, surgeries are invasive procedures, while drug treatments often present with various side effects. Gossypetin, a flavonoid found abundantly in plants such as hibiscus, exhibits anti-oxidant and anti-cancer properties. However, its potential impact on IBD remains unexplored.

Objective: This study aimed to investigate the therapeutic potential of gossypetin on colitis.

Methods: We employed the DSS-induced colitis model to evaluate the therapeutic potential of gossypetin on colitis. The efficacy of gossypetin was assessed within this model using the Disease Activity Index (DAI) score and histological analysis. Additionally, we utilized qRT-PCR to measure the levels of inflammatory cytokines and Superoxide Dismutase (SOD). Immunohistochemistry confirmed the expression of tight junction markers, COX-2, and phosphorylated JNK protein, normally associated with disease progression. Furthermore, Western blot analysis was conducted to examine the SOD levels and anti-apoptotic effects of gossypetin.

Results: In DSS-induced colitis mice, gossypetin treatment ameliorated weight loss and reduced colon length caused by DSS treatment. Additionally, gossypetin-treated groups exhibited DAI scores and reduced histological damage. Moreover, gossypetin treatment increased tight junction expression, decreased inflammatory responses, reduced ROS levels, attenuated JNK signaling, and decreased apoptosis.

Conclusion: Gossypetin shows therapeutic potential for mitigating the symptoms and progression of colitis by targeting ROS-JNK signaling involved in inflammation and tissue damage. This highlights the potential of natural compounds such as gossypetin for targeted therapies with reduced side effects and improved efficacy.

Cancer is a predominant cause of mortality worldwide, necessitating the development of innovative therapeutic techniques. The human microbiome, particularly the gut microbiota, has become a significant element in cancer research owing to its essential role in sustaining health and influencing disease progression. This review examines the microbiome's makeup and essential functions, including immunological modulation and metabolic regulation, which may be evaluated using sophisticated methodologies such as metagenomics and 16S rRNA sequencing. The microbiome influences cancer development by promoting inflammation, modulating the immune system, and producing carcinogenic compounds. Dysbiosis, or microbial imbalance, can undermine the epithelial barrier and facilitate cancer. The microbiome influences chemotherapy and radiation results by modifying drug metabolism, either enhancing or reducing therapeutic efficacy and contributing to side effects and toxicity. Comprehending these intricate relationships emphasises the microbiome's significance in oncology and accentuates the possibility for microbiome-targeted therapeutics. Contemporary therapeutic approaches encompass the utilisation of probiotics and dietary components to regulate the microbiome, enhance treatment efficacy, and minimise unwanted effects. Advancements in research indicate that personalised microbiome-based interventions, have the potential to transform cancer therapy, by providing more effective and customised treatment alternatives. This study aims to provide a comprehensive analysis of the microbiome's influence on the onset and treatment of cancer, while emphasising current trends and future possibilities for therapeutic intervention.

Microneedles have been explored as a novel way of delivering active ingredients into the skin. They have various advantages, such as quick and efficient drug delivery, mechanical stability, minimal pain, variable capacity and easy use. Microneedles are enabled for the delivery of vaccine, peptides, medicinal components and in cosmetology, which couldn't go unnoticed. The novel approaches in the transdermal drug delivery system have increased the efficiency of drug delivery into the skin by crossing the skin barriers. This platform has a wide range of applications and can also be used to deliver non-transdermal biomedicals. The variety in the design of microneedles has demanded similar diversity in their methods of fabrication; micro molding and drawing lithography may be useful methods. There are different types of polymers and materials for the fabrication of microneedles. Several synthetic and natural materials are used in the fabrication of microneedles. Unique shapes, materials, and mechanical properties are modified for organ-specific applications in microneedle engineering. In this review, we discuss several factors and their roles to cross the biological barriers for transdermal drug delivery in various sites, such as in ocular, vascular, oral, and mucosal tissue. Additionally, this article highlights the future scope of transdermal drug delivery systems through microneedles.

Background: Several medicinal plants are identified as therapeutic agents for the world's most deadly disease cancer. A member of the "Cucurbitaceae" family of medicinal plants, Citrullus colocynthis (C. colocynthis) has various pharmacological actions.

Aims and objectives: In the present study we have focused on the phytochemical analysis, antimicrobial, anticancer and in silico investigation of fruit extracts of C. colocynthis. The chloroform, pure ethanolic and aq. ethanolic extracts of C. colocynthis whole fruit, peel and pulp separately have been investigated.

Methods: The phytochemical analysis revealed the presence of alkaloids, flavonoids, steroids, phenols, saponins and glycosides in various parts of the fruit. Some compounds have been identified using GC-MS analysis by comparing with NIST library data. The antimicrobial activity of all extracts was checked by agar well diffusion method against five different bacterial strains such as A. baumannii, K. pneumonia, S. aureus, P. aeruginosa and E. coli. The zone of inhibition (ZOI) ranged between 11 mm to 27 mm against different strains.

Results: The polar solvent extracts (ethanolic and aq. ethanolic extract) of peel showed good sensitivity against all bacterial strains as compared to non-polar solvent (chloroform extract), which showed activity only against Staphylococcus aureus and Pseudomonas aeruginosa. The cytotoxic activity of C. colocynthis all extracts against human brain cancer cell lines (U-87) was assessed using MTT assay.

Conclusion: The % cell viability of ethanolic (ET-PL), and aq. ethanolic extract of whole fruit and pulp showed promising results. The cancerous cell line U-87 seems to be more sensitive towards polar solvents (ethanolic and aq. ethanolic) pulp extracts than peel. Further, based on invitro results, compounds identified in ET-PP were screened for their potential as antibacterial and anticancer agents through molecular docking and MMGBSA studies. These studies strongly supported the in-vitro study results and identified new drug candidates.