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Exploring the Pathogenesis of Alzheimers Disease and Revolutionary Treatment Strategy Based on Nanotechnology
Get PDFAlzheimers disease (AD), a catastrophic disorder that commonly affects the elderly, causes extracellular plaques to form in the hippocampus, leading to slow, progressive loss of brain function. The Blood Brain Barrier poses a significant challenge for conventional drug delivery in AD therapeutics. Therefore, introducing novel strategies such as nanotechnology-based drug delivery offers promising potential. This paper highlights the significance of nanotechnology based drug delivery in AD with respect to its pathophysiology and discusses the current situation and future prospects of the same in diagnosis and therapy. Data collection involved scientific databases such as PubMed, Science Direct, and Google Scholar. The keywords searched were AD, neurodegenerative, nanotechnology, Amyloid-beta protein, tau protein and patents. A total of 146 papers were obtained. The pathophysiology of AD with respect to the Amyloid- and tau hypotheses were found to have significant therapeutic potential. It was also found that nanotechnology systems were able to offer enhanced site-specific action, offering a low toxicity profile in areas where conventional drug delivery systems had difficulty to act on. Delivery systems that were found to have potential were nanoparticles (NPs) including inorganic NPs and magnetic NPs, Quantum Dots, liposomes, dendrimers, Micelles, etc. Thus, our work suggests that NP-based drug delivery systems are able to overcome the challenges faced by conventional systems to achieve therapeutic efficacy with substantial levels of evidence, initiating the much-needed discussions on their potential use in AD therapeutics
CKS2 and Its Interacting Network Induce Tumor Progression with Adverse Effects on Patients Survival in a Pan-Cancer Model
No full textBackground: Cyclin-dependent kinases regulatory subunit 2 (CKS2) has an essential biological function as it binds to the cyclin-dependent kinases catalytic site, which in turn regulates the cell cycle. Hence, malfunction of CKS2 can be finally translated as an irregular cell cycle and malignancy progression. The current study aimed to comprehensively analyze the oncogenic roles of CKS2 in a pan-cancer model focusing on the interference of CKS2 expression with the infiltration of different immune components in the tumor microenvironment. Methods: Here, we applied a comprehensive bioinformatics analysis based on the available data in different databases to investigate the expression levels and the genetic, and epigenetic modifications that occurred to CKS2 and checked the possible correlation of those events with the abundance of immune factors with variable functions. Results: CKS2 was found to be overexpressed in multiple human cancers and that resulted in cancer progression in terms of stage and grade in addition to shorter patients survival under different models. Enhanced infiltration and release of Myeloid-derived suppressor cell (MDSC) and Chemokine ligand 8 (CCL8) with the opposite trend in Natural killer (NK) cells and CCL14 correlated to CKS2 expression was detected as a potential immunological mechanism of CKS2 cancer progression induction. Additionally, the interaction network revealed cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinases regulatory subunit 1B (CKS1B), cell division cycle protein 20 (CDC20), G2/Mitotic-Specific Cyclin-B1 (CCNB1), and G2/Mitotic-Specific Cyclin-B2 (CCNB2) as proteins closely associated with CKS2, where that network represented the molecular mechanism for CKS2 tumor induction. Conclusions: Collectively, the current study nominates CKS2 and a potential biomarker and therapeutic target in a pan-cancer model
Inhibition of the Complement Pathway Induces Cellular Proliferation and Migration in Pancreatic Ductal Adenocarcinoma
No full textBackground: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a growing incidence and mortality despite novel therapeutic strategies. Its aggressiveness and difficulty in treatment suggest the need for a better understanding of associated molecular mechanisms that could be targeted for treatment. The complement signalling pathway may play diverse roles in PDAC by eliciting an immune response, inducing inflammatory responses, and elevating pathways linked to chemoresistance. However, their role in the progression of PDAC is not fully understood. This study aimed to identify potential immune response-related targets in a group of patients. Methods: Thirty tissue samples (tumours and corresponding normal tissues) were obtained from 15 PDAC patients, 34 plasma samples from 25 PDAC patients, six patients with chronic pancreatitis, and three healthy control participants. Targeted pathway-specific polymerase chain reaction (PCR) analysis was conducted to determine the gene expression profiles of immune-response-related genes. The circulating levels of complement proteins C3 and C5 were further investigated. Pharmacological inhibition of the complement pathway in MIA PaCa-2 pancreatic cancer cell lines was performed, and the effect was assessed by cell proliferation, cell migration, and cell cycle assays. Finally, Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) was performed to identify potential molecular mechanisms during inhibition. Results: The results identified C3 as overly expressed in early PDAC compared to later stages in plasma (p = 0.047). Pharmacological inhibition of the complement pathway led to increased cell growth (p < 0.0001), proliferation (p = 0.001) and migration (p = 0.002) in vitro. Proteomic analysis implicated several proteins, such as the mitochondrial and histone proteins, that could play a role in inducing this phenotype. Conclusion: Complement C3 and C5 are elevated in PDAC samples compared to healthy ones. Furthermore, the inhibition of the complement pathway was shown in vitro to result in a more aggressive phenotype by stimulating cellular growth, proliferation, and migration, indicating the involvement of complement C3 and C5 in tumour progression. This study helps to delineate further the role of the complement pathway in PDAC progression
Cytotoxicity, Anticancer Potentials and Anticancer Phytochemicals Present in Viscum continuum E. Mey. Ex Sprague Extracts
No full textBackground: Cancer describes a vast category of diseases our body suffers from. The total global oncology spending was USD186bn as of 2021 and was estimated to rise to USD208.9bn in 2022. The adverse effects of managing cancer with orthodox medications includes death among other dire consequences. Several Viscum species including Viscum album L, Viscum angulatum, and Viscum articulatum Burm f. from other countries have been reported for their anticancer potentials. Methods: Four (n = 4) mistletoe extracts namely n-hexane, dichloromethane, acetone, and methanol were tested for their anti-cancer potemtials against Vero (African green monkey, kidney, non-cancerous), BJ-5ta (Human skin fibroblast), A549 (Human non-small cell lung carcinoma), Michigan Cancer Foundation (MCF7) human breast cancer cell lines. The percentage cancer cells survival rate and selectivity index for each extract were calculated against positive controls (untreated cells) and blank dimethyl sulfoside (DMSO) solutions, and the compounds with anticancer potentials were identified to be present in the extracts using gas chromatography-mass spectrometry analysis. Results: All four extracts showed concentration dependent anti-cancer activity as measured from the percentage average cell viability or cytotoxicity. The cytotoxicity to the lung (A549) was recorded as 1.25, 10, 0.5, 1.25 mg/mL for the hexane, dichloromethane, acetone and methanol extracts respectively. Those for the breast (MCF7) cancer cell lines appeared as as 1.25, 0.5, 0.5 and 10 mg/mL for the hexane, dichloromethane, acetone and methanol extracts in that order. In terms of the selectivity index (SI), that is, which extracts is cytotoxic to a specific cancer cell line, all the extracts were highly selective (SI >2). However, the methanol extract was selectively more toxic to the lung cancer cell (A459) with SI of 6.08 and Half maximal Inhibitory Concentration (IC50) value of 0.251 ± 3.96. The other three extracts were highly selective against breast cancer cell (MCF7) with SI of 5.90 (IC50 = 0.38), 9.06 (IC50 = 0.04) and 8.15 (IC50 = 0.02) for n-hexane, dichloromethane (DCM), and acetone extracts, respectively. Conclusions: Eucalyptol, 9(E),11(E)-conjugated linoleic acid, ester and 9, 12, 15-octadecatrienoic acid detected in South African mistletoe by gas chromatoghraphy-mass spectrometry (GC-MS) analysis is proposed to be responsible for the anticancer potentials of the extracts
Unlocking the Secrets of Probiotics – A Therapeutic Breakthrough for Major Depressive Disorders
No full textThe human gut has 12 distinct phyla, among which Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes make up ˃90%. Depressed individuals are a significant phylum and are differentiated from healthy individuals by their firmicutes. The microbiome is a key component of the pathological basis of major depressive illness as a result of disruption of the microbiota-gut-brain (MGB) axis. The fact is that there is bidirectional communication inside the brain, stomach, and brain-gut, wherein the brain highlights a systemic disease characterized by both brain and peripheral dysfunction. According to the microbiota hypothesis, MGB axis dysfunction is a significant contributor to the pathogenic underpinnings of major depressive disorder (MDD). The etiology of MDD is complicated and includes an imbalance of neurotransmitters, an impaired hypothalamic-pituitary-adrenal (HPA) axis, inflammation, and the MGB axis. According to research, having an aberrant microbiome or a disjointed MGB axis may directly cause psychiatric diseases such as MDD. Hence, resolving these issues may help with depression symptoms. Probiotics may therefore have therapeutic benefits for psychiatric symptoms by fostering healthy and balanced gut flora. The probiotic Bifidobacterium longum NCC3001 has been shown to reduce depression scores. In this review, the unknown mysteries and myths of probiotics are unlocked with special attention given to MDD or depression
The Effects of Pachymic Acid on Colorectal Cancer Cell Proliferation and Metastasis via the MiR-148a-5p/IFI6 Pathway
No full textBackground: Pachymic acid (PA), a purified triterpene extracted from the medicinal fungus Poria cocos, is known for its antiemetic, anti-inflammatory, and antitumor properties. However, the effect of PA on colorectal cancer and its underlying mechanism are yet to be elucidated. In this study, we delved into the chemotherapeutic effects and underlying mechanisms of PA on colorectal cancer. Methods: The impact of PA on the proliferation of cells in colon cancer was investigated employing the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU). Moreover, its role in the migration of colon cancer cells was assessed using the transwell assay. Bioinformatic analysis was performed to predict interferon alpha-inducible protein 6 (IFI6) binding miRNA and dual luciferase assay was used to validate this interaction. The IFI6-overexpressing cell lines were established and used to evaluate if PA regulates IFI6 to affect a serine/threonine protein kinase (AKT) and SMAD Family Member 3 (Smad 3) signaling pathways by western blot between control, PA + Vector and PA + IFI6-overexpression (OE) groups. Furthermore, miR-148a-5p inhibitor was applied to investigate the effect of PA on colorectal cancer cells. Results: PA showed antitumor effects in vitro by inhibiting colon cancer cell proliferation and metastasis in HT29 and DLD-1 cells (p < 0.01). Mechanistically, our data suggested that PA decreased colon cancer cell proliferation and metastasis by increasing miR-148a-5p expression to repress the levels of IFI6, AKT, and Smad 3 signaling pathways (p < 0.05). Moreover, overexpression of IFI6 and administration of miR-148a-5p inhibitors reversed the inhibitory effects of PA on the AKT and Smad-3 pathways (p < 0.01), indicating a critical role for IFI6 in colorectal cancer progression. Conclusion: Our study indicates PA as a potential therapeutic candidate for colorectal cancer growth and metastasis. This study provides a foundation for the potential application of PA in colorectal cancer therapy
PHD Finger Protein 1 (PHF1) as a Novel Marker Regulates Progression of Colon Cancer through Cell Cycle Pathway and Contributes to Immunotherapy
No full textBackgrounds: Colon cancer is a leading cause of fatalities worldwide. The human plant homeodomain (PHD) finger protein 1 (PHF1) has been reported to play roles in various biological processes and the progression of several types of cancer. This study aims to investigate the impact of PHF1 on the progression of colon cancer and explore the underlying mechanisms. Methods: The differential expression of PHF1 in colon cancer tissues and cells was validated using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot analyses. To assess the impact of PHF1 on colon cancer and the cell cycle pathway, as well as the reciprocal effect of cyclin-dependent kinase inhibitor 1A (CDKN1A)-mediated cell cycle regulation on PHF1 in colon cancer, the expression levels of PHF1 and cyclin-dependent kinase inhibitor 1A (CDKN1A) were modulated through specific small interference (si)RNA transfection. Cell proliferation was assessed using colony-forming and cell counting kit-8 (CCK-8) assays, while cell apoptosis was evaluated through the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and enzyme-linked immunosorbent assay (ELISA) to detect Bcl-2 (B-cell Leukemia/Lymphoma 2) and Bax (Bcl-2 associated X protein). Cell metastasis ability was determined using trans-well assays for cell migration and invasion, as well as lipid formation. Human Colorectal Carcinoma Cells (LOVO) were transfected and co-cultured with peripheral blood mononuclear cells (PBMCs) to elucidate the effects of PHF1 and the cell cycle on immunotherapy. This involved assessing the ratio of cells killed by immune cells, the proliferation of CD8+ T cells, and the percentages of CD107a+ and IFN-γ+ T cells. Results: PHF1 was found to be significantly overexpressed in both colon cancer tissues (p < 0.01) and cells (p < 0.01), demonstrating its capacity to activate the cell cycle pathway (p < 0.001). The upregulation of PHF1 led to increased cancer cell proliferation, invasion, and lipid formation (p < 0.001), while simultaneously decreasing colon cancer cell apoptosis (p < 0.001). Importantly, these effects were reversed when the cell cycle was suppressed (p < 0.01). Furthermore, in co-culture experiments where colon cancer cells with upregulated PHF1 were exposed to PBMCs, fewer colon cancer cells were killed (p < 0.001). There was also a reduction in the proliferation of CD8+ T cells (p < 0.001) and lower percentages of both CD8+ CD107a+ T cells (p < 0.001) and CD8+ IFN-γ+ T cells (p < 0.001). Notably, these outcomes were all reversed when the cell cycle pathway was suppressed (p < 0.001). Conclusions: PHF1 emerges as a potential marker for colon cancer, contributing to the progression of the disease through the activation of the cell cycle pathway. The suppression of PHF1 enhances the susceptibility of colon cancer to immunotherapy. These findings underscore the significance of PHF1 and the cell cycle pathway as viable targets for colon cancer treatment. Combining these targets with immunotherapy holds promise for the development of effective therapeutic strategies against colon cancer
Resveratrol Exerts Inhibitory Effects on the Growth and Metastasis of Lung Cancer and Modulates the Polarization of Tumor-Associated Neutrophils
Get PDFBackground: The resveratrol (RES) exhibits inhibitory effects against lung cancer through various targets. However, the exact underlying mechanism remains unclear. This study aims to investigate the effect of RES on the growth and metastasis of lung cancer and its impact on polarization of tumor-associated neutrophils (TANs) and epithelial-mesenchymal transition (EMT). Method: The A549 lung cancer cell line was treated with varying concentrations (0, 5, 10, 20, 40, and 60 μM) of RES. The impact of RES on cellular proliferation was assessed using Cell Counting Kit-8 (CCK-8) assay, and the optimal dosage was selected for subsequent analysis. Furthermore, the effects of RES treatment on the apoptosis, invasion, and migration of the cells, along with its impact on the EMT process, were examined. Neutrophils were isolated from the blood of the health individuals and were co-cultured with A549 cells to investigate the TANs polarization. Additionally, we established a nude mouse model of the subcutaneous tumor. The lung cancer growth, tumor tissue pathology, and tumor cell metastasis were evaluated. Results: We observed that RES effectively suppressed A549 cell growth in a concentration-dependent manner within the dosage range of 10–40 μM (p < 0.001). Furthermore, RES promoted A549 cell apoptosis while limiting invasion and migration (p < 0.001). Moreover, RES was observed to regulate the EMT pathway in A549 cells, thereby limiting its progression (p < 0.01). Notably, RES restricted lung cancer by inducing TANs to polarize toward type N1 while impeding type N2 polarization (p < 0.001). In the nude mouse model, RES demonstrated the above-mentioned effects and considerably reduced lung cancer growth, improved tumor tissue pathology, and limited tumor growth (p < 0.01), as well as reduced the expression of Matrix Metalloproteinase-2 (MMP2) and MMP9 (p < 0.05). Conclusion: Overall, RES effectively reduces lung cancer growth and tumor cell metastasis by boosting N1 polarization of TAN, suppressing N2 polarization, and reducing EMT
ALDH1A3-mTOR Axis May be a Potential Target of Neurological Dysfunction after Deep Hypothermic Circulatory Arrest
No full textBackground: The aldehyde dehydrogenase 1 family member A3 (ALDH1A3)-mammalian target of rapamycin (mTOR) axis has been proven to be a therapeutic target for some tumors. We aimed to investigate the effect of ALDH1A3-mTOR axis on neurological dysfunction after deep hypothermic circulatory arrest (DHCA). Methods: Cardiopulmonary bypass (CPB) models were constructed using Sprague-Dawley (SD) rats, subjected to treatment with normal temperature circulatory arrest (NTCA) or DHCA, or pretreated with rapamycin, and their heart rate and breathing were monitored. The pathological damage of brain tissue was evaluated by hematoxylin and eosin staining. The expression of caveolin-1 (Cav-1) and nuclear factor-kappa B (NF-κB) was detected by quantitative real-time polymerase chain reaction. Oxygen glucose deprivation (OGD) cortical neurons model was employed, followed by treatment with hypothermia, MHY1485, or plasmid transfection as required. The effect of ALDH1A3-mTOR axis on OGD-induced neuronal activity and apoptosis in hypothermia state was detected by cell counting kit-8 (CCK-8) and flow cytometry. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS) level, and mTOR-70 kDa ribosomal protein S6 kinase (P70S6K) activation were determined by 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe, and western blot. Results: Deep hypothermia reduced the heart rate and breathing of CPB rats. CPB aggravated tissue damage, reduced Cav-1 expression and MMP level, but increased ROS level and promoted NF-κB, ALDH1A3 expression and mTOR-P70S6K phosphorylation. Deep hypothermia slightly weakened the nerve damage induced by CPB. Rapamycin had shown a protective effect on the DHCA rat model. In the hypothermia state, silencing ALDH1A3 in vitro increased the cell viability and MMP inhibited by OGD, and reversed the apoptosis, ROS levels, ALDH1A3 expression, and activation of mTOR-P70S6K pathway. Conclusions: Silencing ALDH1A3 protects DHCA rats from nerve damage by inhibiting the mTOR-P70S6K pathway
Exploring Interplay of Polyunsaturated Fatty Acids: A Promising Approach for Treatment of Breast Cancer
No full textCancer, characterized by uncontrolled cell division and potential tissue spread, remains a significant health problem, with breast cancer being the most common in women, accounting for 25% of all cancer cases. Natural compounds have recently gained attention as they can improve the efficacy of cancer treatment. The aim of this study is to shed light on the potential benefits of polyunsaturated fatty acids in the treatment of breast cancer. Overexpression of tyrosine kinase receptors and mutations in the breast cancer gene-1 (BRCA1) and BRCA2 genes lead to breast cancer in women. Based on the findings of papers published in various scientific search engines, n-3 polyunsaturated fatty acid (PUFA) may reduce the likelihood of developing breast cancer due to their anti-inflammatory properties. According to several studies, women who consume more n-3 polyunsaturated fatty acids have a lower risk of breast cancer. n-3 polyunsaturated fatty acids regulate breast cancer by controlling the inflammatory mediators, gene expression transcription factor and signal transducer, peroxisome proliferator-activated receptor-gamma, B-cell lymphoma-2 (Bcl-2) associated X protein or B-cell lymphoma-2, Phosphatidylinositol 3-kinase or Protein kinase B, Nuclear factor-κB, and toll-like receptor-4. Polyunsaturated fatty acids are considered a successful treatment for breast cancer patients when combined with chemotherapy drugs. Doxorubicin is a first-line drug for the treatment of triple-negative breast cancer. Giving doxorubicin and polyunsaturated fatty acids together makes chemotherapy treatments for triple-negative breast cancer work better in the MDA-MB-468 and MDA-MB-231 cell lines. This review highlights the role of PUFAs in modulating cancer-related pathways, offering valuable insights for researchers, clinicians and the pharmaceutical industry in the fight against breast cancer