Advanced pharmaceutical bulletin最新文献

The Warburg effect, first observed by Otto Warburg in the 1920s, delineates a metabolic phenomenon in which cancer cells exhibit heightened glucose uptake and lactate production, even under normoxic conditions. This metabolic shift towards glycolysis, despite the presence of oxygen, fuels the energy demands of rapidly proliferating cancer cells. Dysregulated glucose metabolism, characterized by the overexpression of glucose transporters and the redirection of metabolic pathways towards glycolysis, lies at the crux of this metabolic reprogramming. Consequently, the accumulation of lactate as a byproduct contributes to the creation of an acidic tumor microenvironment, fostering tumor progression and metastasis. However, recent research, notably proposed by Maher Akl, introduces a novel perspective regarding the role of glycolipids in cancer metabolism. Akl's glucolipotoxicity hypothesis posits that aberrant glycolipid metabolism, specifically the intracellular buildup of glycolipids, significantly influences tumor initiation and progression. This hypothesis underscores the disruptive impact of accumulated glycolipids on cellular homeostasis, thereby activating oncogenic pathways and promoting carcinogenesis. This perspective aims to synthesize the intricate mechanisms underlying both the Warburg effect and glucolipotoxicity, elucidating their collective contributions to tumor growth and malignancy. By comprehensively understanding these metabolic aberrations, novel avenues for therapeutic intervention targeting the fundamental drivers of cancer initiation and progression emerge, holding promise for more efficacious treatment strategies in the future.

Liver cancer, specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related deaths, following pancreatic cancer. The 5-year overall survival rate for HCC remains relatively low. Currently, there are multiple treatment options available for HCC, including systemic drugs, minimally invasive local therapies such as radiofrequency ablation, transarterial chemoembolization (TACE), and arterial radioembolization (TARE), as well as surgical interventions like liver resection or transplantation. However, the effectiveness of drug delivery to the cancerous liver is hindered by pathophysiological changes in the organ. In order to address this challenge, lipid-based nanoparticles (LNPs) have emerged as promising platforms for delivering a diverse range of therapeutic drugs. LNPs offer various structural configurations that enhance their physical stability and enable them to accommodate different types of cargo with varying mechanical properties and degrees of hydrophobicity. In this article, we provide a comprehensive review of the current applications of LNPs in the development of anti-HCC therapies. By examining the existing research, we aim to shed light on the potential future directions and advancements in this field.

Purpose: L-asparaginase has been widely recognized as a critical component in the treatment of various types of lymphoproliferative disorders, since its introduction in 1960s. However, its use in some cases leads to allergic reactions rendering the continuation of treatment unfeasible. Thus, the development of L-asparaginase from alternative sources or the production of engineered enzymes have always been considered. This study aimed to produce and evaluate a novel enzyme designed based on the sequence of L-asparaginase from Escherichia coli bacteria with Y176F/S241C mutations.

Methods: The Y176F/S241C mutant L-asparaginase was successfully expressed as the GST-fusion protein in E. coli, and then was subjected to affinity and size exclusion chromatography. The activity of the purified enzyme was determined based on the released ammonia as the result of substrate hydrolysis using Nessler's reagent. Chemical denaturation experiment in the presence of increasing concentration of guanidinium chloride was applied to determine the folding stability of the purified enzyme.

Results: The mutant enzyme was purified with an efficiency of 77-fold but at a low recovery of 0.7%. The determined kinetic parameters Km, Vmax, kcat, specific activity and catalytic efficiency were 13.96 (mM), 2.218 (mM/min), 273.9 (min^-1), 237.8 (IU/mg) and 19.62 (mM^-1 min^-1), respectively. Moreover, unfolding free energy determined by guanidinium chloride induced denaturation for mutated and commercial L-asparaginase enzymes were 8421 J/mol and 5274 J/mol, respectively.

Conclusion: The mutant enzyme showed improved stability over the wild-type. Although the expression level and recovery were low, the mutant L-asparaginase demonstrated promising activity and stability, with potential clinical and industrial applications.

Purpose: We report on the design of hypoxia-induced dual-stage acting dendrimeric nanoparticles (NPs) for selective delivery of two chemotherapeutic model drugs doxorubicin (DOX) and tirapazamin (TPZ) for deepened drug delivery into hypoxic tumors in vitro.

Methods: PAMAM G5 dendrimers were crosslinked with a hypoxic azo linker, attached to a mPEG to form a detachable corona on the dendrimer surface (PAP NPs). NPs were characterized by Zeta sizer, transmission electron microscope (TEM), Fourier transforms infrared (FTIR) and drug release kinetics. The anti-cancer performance of PAPs was evaluated by numerous tests in 2D and 3D cultured MDA-MB-231 breast cancer cells.

Results: MTT assay showed a significant difference between PAP and PAMAMG5 in terms of biocompatibility, and the effect of PAP@DOX was significantly greater than free DOX in hypoxic conditions. The results of DAPI and Annexin V-FITC/PI cell staining also confirmed uniform drug penetration as validated by induction of 90% cell apoptosis in spheroids and a high level of PAP@DOX-induced ROS generation under hypoxia conditions. Mechanistically, PAP@DOX significantly reduced the expression of mTOR, and Notch1, while the expression of Bax and Caspase3 was considerably unregulated, compared to the controls. Importantly, hypoxia-responsive disintegration and hypoxia-induced activation of HAP drug were synergized to promote deep and homogenous HAP distribution in whole microtumor regions to efficiently eliminate residual tumor cells.

Conclusion: Our results indicate the safety and high therapeutic potential of PAP system for targeted drug delivery of chemotherapeutics in particular HAPs which show maximum anti-cancer activity against hypoxic solid tumors.

Purpose: Artificial intelligence (AI), particularly large language models like ChatGPT developed by OpenAI, has demonstrated potential in various domains, including medicine. While ChatGPT has shown the capability to pass rigorous exams like the United States Medical Licensing Examination (USMLE) Step 1, its proficiency in addressing breast cancer-related inquiries-a complex and prevalent disease-remains underexplored. This study aims to assess the accuracy and comprehensiveness of ChatGPT's responses to common breast cancer questions, addressing a critical gap in the literature and evaluating its potential in enhancing patient education and support in breast cancer management.

Methods: A curated list of 100 frequently asked breast cancer questions was compiled from Cancer.net, the National Breast Cancer Foundation, and clinical practice. These questions were input into ChatGPT, and the responses were evaluated for accuracy by two primary experts using a four-point scale. Discrepancies in scoring were resolved through additional expert review.

Results: Of the 100 responses, 5 were entirely inaccurate, 22 partially accurate, 42 accurate but lacking comprehensiveness, and 31 highly accurate. The majority of the responses were found to be at least partially accurate, demonstrating ChatGPT's potential in providing reliable information on breast cancer.

Conclusion: ChatGPT shows promise as a supplementary tool for patient education on breast cancer. While generally accurate, the presence of inaccuracies underscores the need for professional oversight. The study advocates for integrating AI tools like ChatGPT in healthcare settings to support patient-provider interactions and health education, emphasizing the importance of regular updates to reflect the latest research and clinical guidelines.

Purpose: Nowadays, many studies discuss scholarly publishing and associated challenges, but the problem of hijacked journals has been neglected. Hijacked journals are cloned websites that mimic original journals but are managed by cybercriminals. The present study uses a topic modeling approach to analyze published papers in hijacked versions of medical journals.

Methods: A total of 3384 papers were downloaded from 21 hijacked journals in the medical domain and analyzed by topic modeling algorithm.

Results: Results indicate that hijacked versions of medical journals are published in most fields of the medical domain and typically respect the primary domain of the original journal.

Conclusion: The academic world is faced with the third-generation of hijacked journals, and their detection may be more complex than common ones. The usage of artificial intelligence (AI) can be a powerful tool to deal with the phenomenon.

Modern science has been transformed by open access (OA) publishing levied a significant economic burden on the authors. This article analyzes the discrepancies among OA publication fees in pharmacology, toxicology, and pharmaceutics. The observations comprise 160 OA journals and their corresponding Q ranking, SJR, H index, impact factor, country, and cost of publication. The OA fees were found to depend on the quality matrices, which was unexpected. Differences in OA fees raise ethical questions as OA fees are meant to cover the publication charges by the publishers or generate more revenues by taking advantage of the authors' temptation to publish in high-impact journals. Despite our findings being based on limited sample size and belonging to a particular field (pharmacy), it will shed considerable light on the issue of discrepancies among APCs charged by OA journals.

Purpose: Spinal cord injury (SCI) is damage to the spinal cord that resulted in irreversible neuronal loss, glial scar formation and axonal injury. Herein, we used the human amniotic fluid mesenchymal stem cells (hAF-MSCs) and their conditioned medium (CM), to investigate their ability in neuroblast and astrocyte production as well as functional recovery following SCI.

Methods: Fifty-four adult rats were randomly divided into nine groups (n=6), included: Control, SCI, (SCI + DMEM), (SCI + CM), (SCI + MSCs), (SCI + Astrocyte), (SCI + Astrocyte + DMEM), (SCI + Astrocyte + CM) and (SCI + Astrocyte + MSCs). Following laminectomy and SCI induction, DMEM, CM, MSCs, and astrocytes were injected. Western blot was performed to explore the levels of the Sox2 protein in the MSCs-CM. The immunofluorescence staining against doublecortin (DCX) and glial fibrillary acidic protein (GFAP) was done. Finally, Basso-Beattie-Brenham (BBB) locomotor test was conducted to assess the neurological outcomes.

Results: Our results showed that the MSCs increased the number of endogenous DCX-positive cells and decreased the number of GFAP-positive cells by mediating juxtacrine and paracrine mechanisms (P<0.001). Transplanted human astrocytes were converted to neuroblasts rather than astrocytes under influence of MSCs and CM in the SCI. Moreover, functional recovery indexes were promoted in those groups that received MSCs and CM.

Conclusion: Taken together, our data indicate the MSCs via juxtacrine and paracrine pathways could direct the spinal cord endogenous neural stem cells (NSCs) to the neuroblasts lineage which indicates the capability of the MSCs in the increasing of the number of DCX-positive cells and astrocytes decline.