Delivery of siRNAs Against Selective Ion Channels and Transporter Genes Using Hyaluronic Acid-coupled Carbonate Apatite Nanoparticles Synergistically Inhibits Growth and Survival of Breast Cancer Cells.

Introduction: Dysregulated calcium homeostasis and consequentially aberrant Ca2+ signalling could enhance survival, proliferation and metastasis in various cancers. Despite rapid development in exploring the ion channel functions in relation to cancer, most of the mechanisms accounting for the impact of ion channel modulators have yet to be fully clarified. Although harnessing small interfering RNA (siRNA) to specifically silence gene expression has the potential to be a pivotal approach, its success in therapeutic intervention is dependent on an efficient delivery system. Nanoparticles have the capacity to strongly bind siRNAs. They remain in the circulation and eventually deliver the siRNA payload to the target organ. Afterward, they interact with the cell surface and enter the cell via endocytosis. Finally, they help escape the endo-lysosomal degradation system prior to unload the siRNAs into cytosol. Carbonate apatite (CA) nanocrystals primarily is composed of Ca2+, carbonate and phosphate. CA possesses both anion and cation binding domains to target negatively charged siRNA molecules. Methods: Hybrid CA was synthesized by complexing CA NPs with a hydrophilic polysaccharide - hyaluronic acid (HA). The average diameter of the composite particles was determined using Zetasizer and FE-SEM and their zeta potential values were also measured. Results and Discussion: The stronger binding affinity and cellular uptake of a fluorescent siRNA were observed for HA-CA NPs as compared to plain CA NPs. Hybrid CA was electrostatically bound individually and combined with three different siRNAs to silence expression of calcium ion channel and transporter genes, TRPC6, TRPM8 and SLC41A1 in a human breast cancer cell line (MCF-7) and evaluate their potential for treating breast cancer. Hybrid NPs carrying TRPC6, TRPM8 and SLC41A1 siRNAs could significantly enhance cytotoxicity both in vitro and in vivo. The resultant composite CA influenced biodistribution of the delivered siRNA, facilitating reduced off target distribution and enhanced breast tumor targetability.

Adiponectin: A Promising Target for the Treatment of Diabetes and Its Complications.

Diabetes mellitus, a chronic metabolic disorder characterized by hyperglycemia, presents a formidable global health challenge with its associated complications. Adiponectin, an adipocyte-derived hormone, has emerged as a significant player in glucose metabolism and insulin sensitivity. Beyond its metabolic effects, adiponectin exerts anti-inflammatory, anti-oxidative, and vasoprotective properties, making it an appealing therapeutic target for mitigating diabetic complications. The molecular mechanisms by which adiponectin impacts critical pathways implicated in diabetic nephropathy, retinopathy, neuropathy, and cardiovascular problems are thoroughly examined in this study. In addition, we explore possible treatment options for increasing adiponectin levels or improving its downstream signaling. The multifaceted protective roles of adiponectin in diabetic complications suggest its potential as a novel therapeutic avenue. However, further translational studies and clinical trials are warranted to fully harness the therapeutic potential of adiponectin in the management of diabetic complications. This review highlights adiponectin as a promising target for the treatment of diverse diabetic complications and encourages continued research in this pivotal area of diabetes therapeutics.

Understanding the impact of acne vulgaris and associated psychological distress on self-esteem and quality of life via regression modeling with CADI, DLQI, and WHOQoL.

Acne vulgaris (AV) is a psychosomatic disorder and can negatively affect individuals, especially in terms of psychological well-being, self-esteem, and quality of life (QoL). The current study aimed to investigate the association between AV and psychological health, as well as the influence of acne and psychological distress in predicting patients' self-esteem and QoL. This cross-sectional study included 150 patients clinically diagnosed with AV. The severity of acne was measured using GAGS, and following that, patients were instructed to complete the following forms: DASS-21, RSES, CADI, DLQI, and WHOQoL. Female AV patients had significantly higher depression (p = 0.003, t = 3.025) and anxiety (p < 0.001, t = 3.683). Pearson's correlation analysis indicated a strong, positive, and significant correlation between having acne and experiencing depression (r = 0.630), anxiety (r = 0.661), and stress (r = 0.758) (p < 0.001). Multiple regression analysis suggested acne and associated psychological distress had a significant and negative impact on the patient's self-esteem and quality of life. This study highlights the multifaceted consequences of AV and the need to manage its psychological distress. It emphasizes the need for holistic patient care that addresses acne's physical and emotional aspects, with the ultimate goal of enhancing well-being and QoL.

Improved systemic half-life of glucagon-like peptide-1-loaded carbonate apatite nanoparticles in rats.

BACKGROUND: Glucagon-like peptide-1 (GLP1) is an endogenous peptide that regulates blood glucose level. But its susceptibility to rapid metabolic degradation limits its therapeutic use. AIM: To prepare GLP1-encapsulated nanosize particle with controlled release property to improve the systemic half-life of GLP1. METHODS: GLP1 nanoparticles were prepared by complexation of GLP1 with carbonate apatite nanoparticles (CA NPs). The physicochemical properties of the CA NPs, the effects of GLP1-loaded CA NPs on cell viability, and the systemic bioavailability of GLP1 after CA NPs administration were determined. RESULTS: The GLP1-loaded CA NPs was within 200 nm in size and stable in fetal bovine serum. The formulation did not affect the viability of human cell lines suggesting that the accumulation of CA NPs in target tissues is safe. In Sprague Dawley rats, the plasma GLP1 Levels as measured from the GLP1-loaded CA NPs-treated rats, were significantly higher than that of the control rats and free GLP1-treated rats at 1 h post-treatment (P < 0.05), and the level remained higher than the other two groups for at least 4 h. CONCLUSION: The GLP1-loaded CA NPs improved the plasma half-life of GLP1. The systemic bioavailability of GLP1 is longer than other GLP1 nanoparticles reported to date.

Emerging Promise of Computational Techniques in Anti-Cancer Research: At a Glance.

Research on the immune system and cancer has led to the development of new medicines that enable the former to attack cancer cells. Drugs that specifically target and destroy cancer cells are on the horizon; there are also drugs that use specific signals to stop cancer cells multiplying. Machine learning algorithms can significantly support and increase the rate of research on complicated diseases to help find new remedies. One area of medical study that could greatly benefit from machine learning algorithms is the exploration of cancer genomes and the discovery of the best treatment protocols for different subtypes of the disease. However, developing a new drug is time-consuming, complicated, dangerous, and costly. Traditional drug production can take up to 15 years, costing over USD 1 billion. Therefore, computer-aided drug design (CADD) has emerged as a powerful and promising technology to develop quicker, cheaper, and more efficient designs. Many new technologies and methods have been introduced to enhance drug development productivity and analytical methodologies, and they have become a crucial part of many drug discovery programs; many scanning programs, for example, use ligand screening and structural virtual screening techniques from hit detection to optimization. In this review, we examined various types of computational methods focusing on anticancer drugs. Machine-based learning in basic and translational cancer research that could reach new levels of personalized medicine marked by speedy and advanced data analysis is still beyond reach. Ending cancer as we know it means ensuring that every patient has access to safe and effective therapies. Recent developments in computational drug discovery technologies have had a large and remarkable impact on the design of anticancer drugs and have also yielded useful insights into the field of cancer therapy. With an emphasis on anticancer medications, we covered the various components of computer-aided drug development in this paper. Transcriptomics, toxicogenomics, functional genomics, and biological networks are only a few examples of the bioinformatics techniques used to forecast anticancer medications and treatment combinations based on multi-omics data. We believe that a general review of the databases that are now available and the computational techniques used today will be beneficial for the creation of new cancer treatment approaches.

Exploring the Recent Trends in Management of Dementia and Frailty: Focus on Diagnosis and Treatment.

Dementia and frailty increase health adversities in older adults, which are topics of growing research interest. Frailty is considered to correspond to a biological syndrome associated with age. Frail patients may ultimately develop multiple dysfunctions across several systems, including stroke, transient ischemic attack, vascular dementia, Parkinson's disease, Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, cortico-basal degeneration, multiple system atrophy, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. Patients with dementia and frailty often develop malnutrition and weight loss. Rigorous nutritional, pharmacological, and non-pharmacological interventions generally are required for these patients, which is a challenging issue for healthcare providers. A healthy diet and lifestyle instigated at an early age can reduce the risk of frailty and dementia. For optimal treatment, accurate diagnosis involving clinical evaluation, cognitive screening, essential laboratory evaluation, structural imaging, functional neuroimaging, and neuropsychological testing is necessary. Diagnosis procedures best apply the clinical diagnosis, identifying the cause(s) and the condition(s) appropriate for treatment. The patient's history, caregiver's interview, physical examination, cognitive evaluation, laboratory tests, and structural imaging should best be involved in the diagnostic process. Varying types of physical exercise can aid the treatment of these disorders. Nutrition maintenance is a particularly significant factor, such as exceptionally high-calorie dietary supplements and a Mediterranean diet to support weight gain. The core purpose of this article is to investigate trends in the management of dementia and frailty, focusing on improving diagnosis and treatment. Substantial evidence builds the consensus that a combination of balanced nutrition and good physical activity is an integral part of treatment. Notably, more evidence-based medicine knowledge is required.

Stem Cell Transplantation Therapy and Neurological Disorders: Current Status and Future Perspectives.

Neurodegenerative diseases are a global health issue with inadequate therapeutic options and an inability to restore the damaged nervous system. With advances in technology, health scientists continue to identify new approaches to the treatment of neurodegenerative diseases. Lost or injured neurons and glial cells can lead to the development of several neurological diseases, including Parkinson's disease, stroke, and multiple sclerosis. In recent years, neurons and glial cells have successfully been generated from stem cells in the laboratory utilizing cell culture technologies, fueling efforts to develop stem cell-based transplantation therapies for human patients. When a stem cell divides, each new cell has the potential to either remain a stem cell or differentiate into a germ cell with specialized characteristics, such as muscle cells, red blood cells, or brain cells. Although several obstacles remain before stem cells can be used for clinical applications, including some potential disadvantages that must be overcome, this cellular development represents a potential pathway through which patients may eventually achieve the ability to live more normal lives. In this review, we summarize the stem cell-based therapies that have been explored for various neurological disorders, discuss the potential advantages and drawbacks of these therapies, and examine future directions for this field.

Carbonate Apatite Nanoparticles-Facilitated Intracellular Delivery of siRNA(s) Targeting Calcium Ion Channels Efficiently Kills Breast Cancer Cells.

Specific gene knockdown facilitated by short interfering RNA (siRNA) is a potential approach for suppressing the expression of ion channels and transporter proteins to kill breast cancer cells. The overexpression of calcium ion channels and transporter genes is seen in the MCF-7 breast cancer cell line. Since naked siRNA is anionic and prone to nuclease-mediated degradation, it has limited permeability across the cationic cell membrane and short systemic half-life, respectively. Carbonate apatite (CA) nanoparticles were formulated, characterized, loaded with a series of siRNAs, and delivered into MCF-7 and 4T1 breast cancer cells to selectively knockdown the respective calcium and magnesium ion channels and transporters. Individual knockdown of TRPC6, TRPM7, TRPM8, SLC41A1, SLC41A2, ORAI1, ORAI3, and ATP2C1 genes showed significant reduction (p < 0.001) in cell viability depending on the cancer cell type. From a variety of combinations of siRNAs, the combination of TRPC6, TRPM8, SLC41A2, and MAGT1 siRNAs delivered via CA produced the greatest cell viability reduction, resulting in a cytotoxicity effect of 57.06 ± 3.72% (p < 0.05) and 59.83 ± 2.309% (p = 0.09) in 4T1 and MCF-7 cell lines, respectively. Some of the combinations were shown to suppress the Akt pathway in Western Blot analysis when compared to the controls. Therefore, CA-siRNA-facilitated gene knockdown in vitro holds a high prospect for deregulating cell proliferation and survival pathways through the modulation of Ca2+ signaling in breast cancer cells.