Journal of Drug Targeting最新文献

Parkinson's disease (PD) is a central nervous system disease with the highest disability and mortality rate worldwide, and it is caused by a variety of factors. The most common medications for PD have side effects with limited therapeutic outcomes. Many studies have reported that chitosan oligosaccharide (COS) crossed blood-brain barrier to achieve a neuroprotective effect in PD. However, the role of COS in PD remains unclear. The present study demonstrated that COS increased dopaminergic neurons in the substantia nigra (SN) and ameliorated dyskinesia in a PD mouse model. Moreover, COS reduced gut microbial diversity and faecal short-chain fatty acids. Valeric acid supplementation enhanced the inflammatory response in the colon and SN, and it reversed COS - suppressed dopamine neurons damage. Autophagy was involved in COS modulating inflammation through valeric acid. These results suggest that COS reduces bacterial metabolites - valeric acid, which diminishes inflammation via activating autophagy, ultimately alleviating PD.

Various cells in our body regularly divide to replace old cells and dead cells. For a living cell to be growing, cell division and differentiation is highly essential. Cancer is characterised by uncontrollable cell division and invasion of other tissues due to dysregulation in the cell cycle. An accumulation of genetic changes or mutations develops through different physical (UV and other radiations), chemical (chewing and smoking of tobacco, chemical pollutants/mutagens), biological (viruses) and hereditary factors that can lead to cancer. Now, cancer is considered as a major death-causing factor worldwide. Due to advancements in technology, treatment like chemotherapy, radiation therapy, bone marrow transplant, immunotherapy, hormone therapy and many more in the rows. Although, it also has some side effects like fatigue, hair fall, anaemia, nausea and vomiting, constipation. Modern improved drug therapies come with severe side effects. There is need for safer, more effective, low-cost treatment with lesser side-effects. Biologically active natural products derived from plants are the emerging strategy to deal with cancer proliferation. Moreover, they possess anti-carcinogenic, anti-proliferative and anti-mutagenic properties with reduced side effects. They also detoxify and remove reactive substances formed by carcinogenic agents. In this article, we discuss different plant-based products and their mechanism of action against cancer.

In this study, a novel selenium@zeolitic imidazolate framework core/shell nanocomposite stabilised with alginate was used to improve the anti-tumour activity of curcumin. The developed alginate-stabilised curcumin-loaded selenium@zeolitic imidazolate framework (Alg@Cur@Se@ZIF-8) had a mean diameter of 159.6 nm and polydispersity index < 0.25. The release of curcumin from the nanocarrier at pH 5.4 was 2.69 folds as high as at pH 7.4. The bare nanoparticles showed haemolytic activity of about 12.16% at a concentration of 500 µg/mL while covering their surface with alginate reduced this value to 5.2%. By investigating cell viability, it was found that Alg@Cur@Se@ZIF-8 caused more cell death than pure curcumin. Additionally, in vivo studies showed that Alg@Cur@Se@ZIF-8 dramatically reduced tumour growth compared to free curcumin in 4T1 tumour-bearing mice. More importantly, the histological study confirmed that the developed drug delivery system successfully inhibited lung and liver metastasis while causing negligible toxicity in vital organs. Overall, due to the excellent inhibitory activity on cancerous cell lines and tumour-bearing animals, Alg@Cur@Se@ZIF-8 can be considered promising for breast cancer therapy.

Rheumatoid arthritis is a chronic and complex autoimmune disease that is marked by an inflammatory response, synovial hyperplasia, vascularisation, fascial formation, cartilage and bone destruction, which can lead to joint deformity and even loss of function, ultimately affecting a person's health and quality of life. Although the pathogenesis of RA is unclear, growing evidence suggests that inflammation-associated cells infiltrate joints, causing tissue damage, inflammation and pain. This disruption in the balance between host tolerance and immune homeostasis the progression of RA. Existing drug therapy and surgical treatments for RA are unable to completely cure the disease or reverse its accelerated progression. Therefore, the design and development of an appropriate and effective drug delivery system will substantially improve the therapeutic effect. In this review, by describing the inflammatory microenvironment of rheumatoid arthritis and the associated inflammatory cells, the progress of targeting strategies and applications of nanotechnology in the disease is summarised, which will be helpful in providing new ideas for the subsequent treatment of rheumatoid arthritis.

Background: Blocking Transient Receptor Potential Melastatin 4 (TRPM4) in rodents by our antibody M4P has shown to attenuate cerebral ischaemia-reperfusion injury. Since M4P does not interact with human TRPM4, the therapeutic potential of blocking human TRPM4 remains unclear. We developed a monoclonal antibody M4M that inhibited human TRPM4 in cultured cells. However, M4M has no effect on stroke outcome in wild-type rats. Therefore, M4M needs to be evaluated on animal models expressing human TRPM4.

Methods: We generated a humanised rat model using the CRISPR/Cas technique to knock-in (KI) the human TRPM4 antigen sequence.

Results: In primary neurons from human TRPM4 KI rats, M4M binds to hypoxic neurons, but not normoxic nor wild-type neurons. Electrophysiological studies showed that M4M blocked ATP depletion-induced activation of TRPM4 and inhibited hypoxia-associated cell volume increase. In a stroke model, administration of M4M reduced infarct volume in KI rats. Rotarod test and Neurological deficit score revealed improvement following M4M treatment.

Conclusion: M4M selectively binds and inhibits hypoxia-induced human TRPM4 channel activation in neurons from the humanised rat model, with no effect on healthy neurons. Use of M4M in stroke rats showed functional improvements, suggesting the potential for anti-human TRPM4 antibodies in treating acute ischaemic stroke patients.