The aim is to test the hypothesis whether the cholesterol loaded lysosomes are capable of mediating lysosomal membrane permeabilization (LMP) during aging and to study the efficacy of epigallocatechin-3-gallate (EGCG) in preserving the lysosomal membrane stability. Aged rats were fed with high cholesterol diet (HCD) and treated with EGCG orally. Serum and tissue lipid status, cholesterol levels in lysosomal fraction, activities of lysosomal enzymes in lysosomal, and cytosolic fractions were measured. Transmission electron microscopic studies (TEM), oil red "O" (ORO) staining, and immunohistochemical analysis of oxidized low density lipoprotein (OxLDL) were carried out. Significant increase in serum, tissue lipid profile, and lysosomal cholesterol levels were observed in aged HCD-fed rats with a concomitant decrease in high density lipoprotein (HDL) levels. We also observed a significant increase in lipid accumulation in hepatocytes of aged HCD-fed rats by TEM, ORO, and immunohistochemical staining. Upon treatment with EGCG to aged HCD-fed animals, we found augmented levels of HDL with a concomitant decrease in lysosomal cholesterol levels and other lipoproteins. TEM studies and immunohistochemistry of OxLDL also showed a marked reduction in lipid deposition of hepatocytes. Thus, EGCG has preserved the lysosomal membrane stability in HCD stressed aged rats. SIGNIFICANCE OF THE STUDY: The research article is focused mainly on the effect of EGCG and its capability on mitigating the release of lysosomal enzymes in aged animals fed with HCD. The study signifies the cellular function of the organelle lysosome following administration of aged rats with HCD, which would make the readers to understand the action of EGCG and the interrelationship of both cholesterol and activity of lysosomes when cholesterol is loaded.
Adipose tissue is an enormously active endocrine organ, secreting various hormones, such as adiponectin, leptin, resistin and visfatin, together with classical cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). All these adipocytokines play significant roles in the regulation of energy metabolism, glucose and lipid metabolism, reproduction, cardiovascular function and immunity. Adipocytokines are significantly regulated by nutritional status and can directly influence other organ systems, including brain, liver and skeletal muscle. Adiponectin plays a key role as an anti-inflammatory hormone. Upregulated expression of resistin, vaspin, apelin and TNF-α plays a significant role in induction of insulin resistance linked with obesity and type 2 diabetes. Ghrelin, the circulating peptide, has been found to stimulate appetite and regulate energy balance. Thus, it can be considered 1 of the candidate genes for obesity and type 2 diabetes. Omentin is a novel adipokine produced by visceral adipose tissue. Circulating levels of omentin are decreased in insulin-resistant states, for example, in obesity and diabetes. IL-6 plays a vital role in regulating the accumulation of lipids intramyocardially. Based on the biologic relevance of these adipocytokines, they can no longer be considered as energy storage sites alone but must also be considered in metabolic control. Hence, the present review summarizes the regulatory roles of adipocytokines in diabetes linked with obesity.
Diabetic retinopathy (DR) is classically defined by its vascular lesions and damage in the neurons of the retina. The cellular and clinical elements of DR have many features of chronic inflammation. Understanding the individual cell-specific inflammatory changes in the retina may lead to novel therapeutic approaches to prevent vision loss. The systematic use of available pharmacotherapy has been reported as a useful adjunct tool to laser photocoagulation, a gold standard therapy for DR. Direct injections or intravitreal anti-inflammatory and antiangiogenesis agents are widely used pharmacotherapy to effectively treat DR and diabetic macular edema (DME). However, their effectiveness is short term, and the delivery system is often associated with adverse effects, such as cataract and increased intraocular pressure. Further, systemic agents (particularly hypoglycemic, hypolipidemic, and antihypertensive agents) and plants-based drugs have also provided promising treatment in the progression of DR. Recently, advancements in pluripotent stem cells technology enable restoration of retinal functionalities after transplantation of these cells into animals with retinal degeneration. This review paper summarizes the developments in the current and potential pharmacotherapy and therapeutic technology of DR. Literature search was done on online databases, PubMed, Google Scholar, clinitrials.gov, and browsing through individual ophthalmology journals and leading pharmaceutical company websites.
The present study was aimed to investigate the antioxidant and cytotoxicity activity against HCT-15 of fucoidan from Sargassum cinereum. Purification of fucoidan was done by DEAE cellulose and dialysis. Physicochemical characterization of fucoidan was analysed by calorimetric assay, FT-IR, HPLC and NMR. The extracted fucoidan contains 65.753% of fucose and 3.7±1.54% of sulphate respectively. HPLC results showed that the fucoidan contains the monosaccharide composition such as fucose, galactose, mannose and xylose. Antioxidant effect of fucoidan in Sargassum Cinereum was determined by DPPH. The maximum DPPH activity was found at the concentration of 100μg, where as the crude extract showed the scavenging activity was 63.58±0.56%. Cytotoxicity effect was done by MTT assay. Fucoidan extract caused about 50% of cell death after 24h of incubation with 75±0.9037μg/ml against HCT-15.
Gefitinib (GET) is a revolutionary targeted treatment inhibiting the epidermal growth factor receptor's tyrosine kinase action by competitively inhibiting the ATP binding site. In preclinical trials, several lung cancer cell lines and xenografts have demonstrated potential activity with GET. Response rates neared 25% in preclinical trials for non-small cell lung cancer. Here, we describe the one-pot synthesis of GET@ZIF-8 nanocomposites (NCs) in pure water, encapsulating zeolitic imidazolate framework 8 (ZIF-8). This method developed NCs with consistent morphology and a loading efficiency of 9%, resulting in a loading capacity of 20 wt%. Cell proliferation assay assessed the anticancer effect of GET@ZIF-8 NCs on A549 and H1299 cells. The different biochemical staining (Calcein-AM and PI and 4',6-Diamidino-2-phenylindole nuclear staining) assays assessed the cell death and morphological examination. Additionally, the mode of apoptosis was evaluated by mitochondrial membrane potential (∆ψm) and reactive oxygen species. Therefore, the study concludes that GET@ZIF-8 NCs are pledged to treat lung cancer cells.
Globally, cancer is the leading cause of death and morbidity, and skin cancer is the most common cancer diagnosis. Skin problems can be treated with nanoparticles (NPs), particularly with zinc oxide (ZnO) NPs, which have antioxidant, antibacterial, anti-inflammatory, and anticancer properties. An antibacterial activity of zinc oxide nanoparticles prepared in the presence of 4-nitrobenzaldehyde (4NB) was also tested in the present study. In addition, the influence of synthesized NPs on cell apoptosis, cell viability, mitochondrial membrane potential (MMP), endogenous reactive oxygen species (ROS) production, apoptosis, and cell adhesion was also examined. The synthesized 4-nitro benzaldehyde with ZnO (4NBZnO) NPs were confirmed via characterization techniques. 4NBZnO NPs showed superior antibacterial properties against the pathogens tested in antibacterial investigations. As a result of dose-based treatment with 4NBZnO NPs, cell viability, and MMP activity of melanoma cells (SK-MEL-3) cells were suppressed. A dose-dependent accumulation of ROS was observed in cells exposed to 4NBZnO NPs. As a result of exposure to 4NBZnO NPs in a dose-dependent manner, viable cells declined and apoptotic cells increased. This indicates that apoptotic cell death was higher. The cell adhesion test revealed that 4NBZnO NPs reduced cell adhesion and may promote apoptosis of cancer cells because of enhanced ROS levels.
The current investigation focuses on synthesizing copper oxide (CuO)-titanium oxide (TiO2 )-chitosan-farnesol nanocomposites with potential antibacterial, antifungal, and anticancer properties against Melanoma cells (melanoma cells [SK-MEL-3]). The nanocomposites were synthesized using the standard acetic acid method and subsequently characterized using an X-ray diffractometer, scanning electron microscope, transmission electron microscopy, and Fourier transform infrared spectroscopy. The results from the antibacterial tests against Streptococcus pneumoniae and Stapylococcus aureus demonstrated significant antibacterial efficacy. Additionally, the antifungal studies using Candida albicans through the agar diffusion method displayed a considerable antifungal effect. For evaluating the anticancer activity, various assays such as MTT assay, acridine orange/ethidium bromide dual staining assay, reactive oxygen species (ROS) generation assay, and mitochondrial membrane potential (MMP) analysis were conducted on SK-MEL-3 cells. The nanocomposites exhibited the ability to induce ROS generation, decrease MMP levels, and trigger apoptosis in SK-MEL-3 cells. Collectively, the findings demonstrated a distinct pattern for the synthesized bimetallic nanocomposites. Furthermore, these nanocomposites also displayed significant (p
Electronic cigarettes (e-cigarettes) have emerged as a potential alternative to traditional smoking and may aid in tobacco harm reduction and smoking cessation. E-cigarette use has notably increased, especially among young non-tobacco users, raising concerns due to the unknown long-term health effects. The oral cavity is the first and one of the most crucial anatomical sites for the deposition of e-cigarette aerosols. E-cigarette aerosols contain nicotine, flavors, volatile organic compounds, heavy metals, carcinogens, and other hazardous substances. These aerosols impact the oral cavity, disrupting host-microbial interactions and triggering gingivitis and systemic diseases. Furthermore, oral inflammation and periodontitis can be caused by proinflammatory cytokines induced by e-cigarette aerosols. The toxic components of e-cigarette aerosols increase the cellular reactive oxygen species (ROS) levels, reduce antioxidant capacity, increase DNA damage, and disrupt repair processes, which may further contribute to harmful effects on oral epithelum, leading to inflammatory and pre-malignant oral epithelial lesions. In this review, we analyze the toxicological properties of compounds in e-cigarette aerosols, exploring their cytotoxic, genotoxic, and inflammatory effects on oral health and delving into the underlying molecular mechanisms. Further research is essential to understand the impact of e-cigarettes on oral health and make informed regulatory decisions based on reliable scientific evidence.
Medicinal plants as rich sources of bioactive compounds are now being explored for drug development against COVID-19. 19 medicinal plants known to exhibit antiviral and anti-inflammatory effects were manually curated, procuring a library of 521 metabolites; this was virtually screened against NSP9, including some other viral and host targets and were evaluated for polypharmacological indications. Leads were identified via rigorous scoring thresholds and ADMET filtering. MM-GBSA calculation was deployed to select NSP9-Lead complexes and the complexes were evaluated for their stability and protein-ligand communication via MD simulation. We identified 5 phytochemical leads for NSP9, 23 for Furin, 18 for ORF3a, and 19 for IL-6. Ochnaflavone and Licoflavone B, obtained from Lonicera japonica (Japanese Honeysuckle) and Glycyrrhiza glabra (Licorice), respectively, were identified to have the highest potential polypharmacological properties for the aforementioned targets and may act on multiple pathways simultaneously to inhibit viral entry, replication, and disease progression. Additionally, MD simulation supports the robust stability of Ochnaflavone and Licoflavone B against NSP9 at the active sites via hydrophobic interactions, H-bonding, and H-bonding facilitated by water. This study promotes the initiation of further experimental analysis of natural product-based anti-COVID-19 therapeutics.
Nanocomposites selectively induce cancer cell death, holding potential for precise liver cancer treatment breakthroughs. This study assessed the cytotoxicity of gold nanocomposites (Au NCs) enclosed within silk fibroin (SF), aptamer (Ap), and the myogenic Talaromyces purpureogenus (TP) against a human liver cancer cell (HepG2). The ultimate product, Ap-SF-TP@Au NCs, results from a three-step process. This process involves the myogenic synthesis of TP@Au NCs derived from TP mycelial extract, encapsulation of SF on TP@Au NCs (SF-TP@Au NCs), and the conjugation of Ap within SF-TP@Au NCs. The synthesized NCs are analyzed by various characteristic techniques. Ap-SF-TP@Au NCs induced potential cell death in HepG2 cells but exhibited no cytotoxicity in non-cancerous cells (NIH3T3). The morphological changes in cells were examined through various biochemical staining methods. Thus, Ap-SF-TP@Au NCs emerge as a promising nanocomposite for treating diverse cancer cells.
The engineered nano-vehicle was constructed using magnetic iron oxide nanoparticles (MIONs) and chitosan (CTS) to stabilize anticancer agent vanillic acid (VNA) which was loaded on CTS-coated MIONs nanocarrier, and more importantly, to achieve sustained VNA release and subsequent proper anticancer activity. The new thermally stable VNA-CTS- MIONs nanocomposite was spherical with a middle diameter of 6 nm and had a high drug loading of about 11.8 %. The MIONs and resulting nanocomposite were composed of pure magnetite and therefore, were superparamagnetic with saturation magnetizations of 53.3 and 45.7 emu.g-1, respectively. The release profiles of VNA from VNA-CTS-MIONs nanocomposite in different pH values were sustained and showed controlled pH-responsive delivery of the loaded VNA with 89 % and 74 % percentage release within 2354 and 4046 min at pH 5 and 7.4, respectively, as well as were in accordance with the pseudo-second-order model. The VNA-CTS-MIONs nanocomposite treatment at diverse concentrations remarkably decreased the viability and promoted ROS accumulation and apoptosis in the MDA-MB-231 breast cancer cells. Hence, it can be a propitious candidate for the management of breast cancer in the future.
Bacterial Extracellular Vesicles (BEVs) possess the capability of intracellular interactions with other cells, and, hence, can be utilized as an efficient cargo for worldwide delivery of therapeutic substances such as monoclonal antibodies, proteins, plasmids, siRNA, and small molecules for the treatment of neurodegenerative diseases (NDs). BEVs additionally possess a remarkable capacity for delivering these therapeutics across the blood-brain barrier to treat Alzheimer's disease (AD). This review summarizes the role and advancement of BEVs for NDs, AD, and their treatment. Additionally, it investigates the critical BEV networks in the microbiome-gut-brain axis, their defensive and offensive roles in NDs, and their interaction with NDs. Furthermore, the part of BEVs in the neuroimmune system and their interference with ND, as well as the risk factors made by BEVs in the autophagy-lysosomal pathway and their potential outcomes on ND, are all discussed. To conclude, this review aims to gain a better understanding of the credentials of BEVs in NDs and possibly discover new therapeutic strategies.
Extracellular clustering of amyloid-β (Aβ) and an impaired autophagy lysosomal pathway (ALP) are the hallmark features in the early stages of incurable Alzheimer's disease (AD). There is a pressing need to find or develop new small molecules for diagnostics and therapeutics for the early stages of AD. Herein, we report a small molecule, namely F-SLCOOH, which can bind and detect Aβ1-42, Iowa mutation Aβ, Dutch mutation Aβ fibrils and oligomers exhibiting enhanced emission with high affinity. Importantly, F-SLCOOH can readily pass through the blood-brain barrier and shows highly selective binding toward the extracellular Aβ aggregates in real-time in live animal imaging of a 5XFAD mice model. In addition, a high concentration of F-SLCOOH in both brain and plasma of wildtype mice after intraperitoneal administration was found. The ex vivo confocal imaging of hippocampal brain slices indicated excellent colocalization of F-SLCOOH with Aβ positive NU1, 4G8, 6E10 A11 antibodies and THS staining dye, affirming its excellent Aβ specificity and targetability. The molecular docking studies have provided insight into the unique and specific binding of F-SLCOOH with various Aβ species. Importantly, F-SLCOOH exhibits remarkable anti-fibrillation properties against toxic Aβ aggregate formation of Aβ1-42, Iowa mutation Aβ, and Dutch mutation Aβ. F-SLCOOH treatment also exerts high neuroprotective functions and promotes autophagy lysosomal biogenesis in neuronal AD cell models. In summary, the present results suggest that F-SLCOOH is a highly promising theranostic agent for diagnosis and therapeutics of AD.