Current Pharmaceutical Design - Volume 29, Issue 4, 2023

Metallic nanoparticles (MNPs) have been widely used for diagnostic and therapeutic purposes in clinical practice. A number of MNP formulations are being investigated in clinical trials for various applications. This increase in the use of NPs results in higher exposure to humans, leading to toxicity issues. Hence, it is necessary to determine the possible undesirable effects of the MNPs after in-vivo application and exposure. One of the main reasons for the toxicity of MNPs is the release of their respective metallic ions throughout the body. Many research studies are in progress investigating the various strategies to reduce the toxicity of MNPs. These research studies aim to change the size, dose, agglomeration, release, and excretion rates of MNPs. In this perspective review, we discussed the possible strategies to improve the therapeutic effects of MNPs through various processes, with lessons learned from the studies involving silver nanoparticles (AgNPs). We also discussed the ways to manage the toxicity of MNPs by purification, surface functionalization, synergistic effect, and targeted therapy approach. All these strategies could reduce the dose of the MNPs without compromising their therapeutic benefits, which could decrease the toxicity of MNPs. Additionally, we briefly discussed the market and toxicology testing for FDA-regulated MNPs.

Neurodegenerative diseases are chronic and progressive disease groups characterized by the decline of neural transmission because of the loss of structure and function of neurons. Although there is currently no effective treatment for neurodegenerative diseases, new treatment strategies need to be developed urgently. Among neurotrophins, BDNF has been extensively investigated, and it has emerged as an important regulator of synaptic plasticity, neuronal survival, and differentiation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases. Moreover, promising results have been obtained for BDNF in many experimental studies on animal models. In addition, BDNF serves as a crucial molecular target for developing drugs to treat neurological diseases. However, several pharmacokinetic difficulties have limited its use in clinical practice, such as its inability to cross the blood-brain barrier, short half-life, and potential adverse effects. To avoid these difficulties, several approaches have been explored, but they have led to disappointing results. One way to overcome the limitations of BDNF may be with mimetic molecules that can effectively stimulate the receptors it has an affinity with and thus activates BDNF pathways. In this perspective article, an evaluation of the efficacy of different BDNF mimetics against neurodegenerative diseases was made.

Objective: Using perioperative VTE prophylactic anticoagulant pathway delicacy management, we aimed to explore the role of clinical pharmacists in perioperative VTE prophylactic anticoagulant treatment and the effect of the clinical medicine pathway implementation. Methods: In compliance with evidence-based medicine, combined with clinical practice, clinical pharmacists participated in the formulation of the perioperative anticoagulant clinical medicine pathway. The PDCA cycle was strictly implemented. Urologic Department, Affiliated Hospital of Qingdao University, Qingdao Shandong, China, served as a pilot department for the evaluation of the effect of drug clinical pathway implementation. Results: The anticoagulant clinical medicine pathway for the urologic department was formulated and implemented from October 2020 to August 2021. The entry rate gradually increased, and the accuracy of thrombosis risk assessment improved. The proportion of drugs in the department and the per capita drug cost decreased significantly. Conclusion: The perioperative VTE prophylactic anticoagulant pathway showed significant achievements in the rational use of urologic anticoagulant drugs, lowering the cost of medical care. Therefore, it could be considered a novel long-term mechanism for rational analgesia drug use.

The considerable burden of colorectal cancer and the increasing prevalence in young adults emphasizes the necessity of understanding its underlying mechanisms and risk factors as well as providing more effective treatments. There is growing evidence of a positive relationship between obesity and colorectal cancer. Furthermore, the prominent role of gut microbiota dysbiosis in colorectal carcinogenesis is becoming more evident. Sequencing studies demonstrate an altered composition and ecology of intestinal microorganisms in both colorectal cancer and obese patients and have pinpointed some specific bacteria as the key role players. The purpose of this review is to provide a general outlook of how gut microbiota may impact the initiation and promotion of colorectal cancer and describes probable links between gut microbiota and obesity. We also provide evidence about targeting the microbiota as an intervention strategy for both ameliorating the risk of cancer and augmenting the therapy efficacy.

Bacteria-caused diseases continue to pose a serious threat to human health. The current situation of overused antibiotics against those diseases further spurs and exacerbates the ever-increasing drug resistance problems, which really leaves us very few options to combat those nasty bugs. Gene therapies based on the antisense oligonucleotide, though developed more than 40 years ago, did not reform the current treatments as originally expected. Along with the advances of new delivery technologies, this old field thrives again. In addition, newly evolving gene-editing tools based on the CRISPR-Cas system shed new light on this old field, bringing a breeze of hope to gene therapies for bacteria-caused diseases. As a fast-growing field, we strive to summarize in this review the recent progress in using gene therapies in those areas, analyze the potential challenges or problems from using antisense or gene-editing tools for targeting bacterial diseases and seek to explore any potential solutions to the current dilemmas. As a short review, we will focus our discussion mainly on antisense oligonucleotide-based gene therapies while briefly touching on the CRISPR-Cas based ones as the latter is just beginning to get more attention for application in the prokaryotic kingdom.

Aim: We aimed to design RGD-anchored liposomes encapsulating an antipyroptosis drug that could efficiently target macrophages and relieve the rate of cytokine release syndrome, providing a new strategy for sepsis treatment, especially sepsis-induced acute renal injury. Background: Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by host response disorders due to infection. Sepsis has a high incidence and remains one of the leading causes of death worldwide. Objective: Macrophage-mediated pyroptosis plays an important role in the occurrence and development of cytokine release syndrome and organ injury caused by sepsis. Curcumin can inhibit inflammasome assembly and slow the progression of pyroptosis by scavenging intracellular reactive oxygen species, but it has poor water solubility and low bioavailability. The emergence of drug-delivery nanosystems has overcome this problem, but there is still a lack of research on how to accurately deliver antipyroptotic drugs to innate immune cells and subsequently hinder pyroptosis. Methods: We constructed a curcumin-loaded RGD-modified liposome (RGD-lipo/Cur) and demonstrated that RGD-lipo/Cur could effectively target macrophages. Results: In vitro, RGD-lipo/Cur reduced the upregulation of caspase-1, caspase-3, NLRP3, IL-1β and GSDMD, inhibiting pyroptosis, reducing oxidative stress, and attenuating the proinflammatory cytokine cascade. Conclusion: RGD-lipo/Cur was considered to have great potential for sepsis treatment.

Background: Immune checkpoint inhibitors (ICI) foster T lymphocytes to fight cancer, but they can also trigger immune-related adverse events (irAE) in various organs, including thyroid dysfunction that can manifest itself in terms of both hyperthyroidism and hypothyroidism or subclinical disease. Objective: Based on previous observations, this study evaluated the impact of oncological immunotherapy on the development of thyroid dysfunction in a cohort of patients treated with ICI at our institution. Methods: We collected 10 cases of thyroid irAE that emerged from 24 cancer patients treated with immunotherapy, belonging to a cohort of 120 patients who were sent to our clinic by the Oncology Department of our institution, between December 2016 and March 2020. Results: From the analysis of the data, thyroid irAEs emerged after a median time of 9 weeks, and they occurred mainly in females. Regardless of the initial presentation (thyroiditis with thyrotoxicosis, hypothyroidism, or worsening of the previous subclinical hypothyroidism), later all patients developed persistent hypothyroidism which required hormone replacement therapy with levothyroxine. This finding was confirmed by a statistically significant increase in the median value of TSH (thyroid-stimulating hormone) between the pre-ICI treatment and subsequent phases and, for the first time, by a reduction in the median value of the thyroid volume estimated by neck ultrasound, a sign of destructive thyroiditis. Conclusion: Our results confirm that patients undergoing immunotherapy should be monitored for potential thyroid dysfunction with biochemical assessments and changes in thyroid volume estimated by ultrasound could be helpful in the diagnostic work-up.

Background: Angiopoietin-like protein 4 (Angptl4) is a glycoprotein that is involved in regulating lipid metabolism, which has been indicated as a link between hypertriglyceridemia and albuminuria in glomerulonephropathy. Deregulated lipid metabolism is increasingly recognized as an important risk factor of glomerulonephropathy. This study aimed to investigate the Angptl4 expression in renal tissue and podocyte under hyperlipidemia conditions and explore the potential molecular mechanisms. Objective: The role of Angptl4 in hyperlipidemia-induced glomerular disease and the detailed underlying mechanisms are unclear. This study sought new insights into this issue. Methods: We measured Angptl4 levels in the plasma and urine from patients with hyperlipidemia and healthy people. Rats were fed a high fat diet (HFD) to induce dyslipidemia model and the human podocytes were stimulated by palmitic acid as in vivo and in vitro experiments. The podocytes injury and the Angptl4 level in renal tissues were evaluated. Furthermore, the mechanism of Angptl4 on podocytes injury was investigated. Results: The urinary Angptl4 level was gradually upregulated in both patients with hyperlipidaemia and high fat-diet-induced rats. HFD rats showed increased 24 h urinary protein and glomerular tuft area at week 12. The levels of nephrin and WT-1 were down-regulated, but the Angptl4 levels were markedly upregulated on the glomerular of rats on HFD. In the human podocytes, lipid accumulation accompanied by increases of Angptl4, but the expression of nephrin, WT-1, p-AMPKα and p-ACC was decreased after palmitic acid treatment. However, this injury effect was mediated by the aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR), activator of the low energy sensor AMPK/ACC signaling. Conclusion: This study was the first of its kind to show that podocyte damage induced by dyslipidemia could be associated with upregulated Angptl4 and that patients with hyperlipidemia might have relatively high urinary Angptl4 expression. The dysregulation of Angptl4 in the podocytes under hyperlipidemia is possibly carried out through AMPK/ACC signaling pathway.