Search Results (37,338)

Inositol hexakisphosphate (InsP₆) is the most abundant inositol polyphosphate both in plant and animal cells. Exogenous InsP₆ is known to inhibit cell proliferation and induce apoptosis in cancerous cells. However, cellular entry of exogenous InsP₆ is hindered due to the presence of highly negative charge on this molecule. Therefore, to enhance the cellular delivery of InsP₆ in cancerous cells, InsP₆ was encapsulated by chitosan (CS), a natural polysaccharide, via the ionic gelation method. Our hypothesis is that encapsulated InsP₆ will enter the cell more efficiently to trigger its apoptotic effects. The incorporation of InsP₆ into CS was optimized by varying the ratios of the two and confirmed by InsP₆ analysis via polyacrylamide gel electrophoresis (PAGE) and atomic absorption spectrophotometry (AAS). The complex was further characterized by Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FTIR) for physicochemical changes. The data indicated morphological changes and changes in the spectral properties of the complex upon encapsulation. The encapsulated InsP₆ enters human breast cancer MCF-7 cells more efficiently than free InsP₆ and triggers apoptosis via a mechanism involving the production of reactive oxygen species (ROS). This work has potential for developing cancer therapeutic applications utilizing natural compounds that are likely to overcome the severe toxic effects associated with synthetic chemotherapeutic drugs. Full article

Mycotoxin contamination of cereals and cereal-based products is a serious problem for food safety. Antioxidant-rich ingredients such as bilberries (Vaccinium myrtillus L., VM) may mitigate their harmful effects. Firstly, total phenolic content, antioxidant activity, and analytical phytochemical composition (hydroxycinnamic and hydroxybenzoic acids, flavanols, flavonols, and anthocyanins) were assessed in lyophilized wild bilberries from Romania. Secondly, this study evaluated bilberries’ effects on reducing ochratoxin A (OTA) bioaccessibility and cytotoxicity. An in vitro digestion model was developed and applied to four different types of bread: Control, VM (2%), OTA (15.89 ± 0.13 mg/kg), and OTA (16.79 ± 0.55 mg/kg)-VM (2%). The results indicated that VM decreased OTA bioaccessibility by 15% at the intestinal level. OTA-VM digests showed improved Caco-2 cell viability in comparison to OTA digests across different exposure times. Regarding the alterations in Jurkat cell line cell cycle phases and apoptosis/necrosis, significant increases in cell death were observed using OTA digests (11%), while VM addition demonstrated a protective effect (1%). Reactive oxygen species (ROS) analysis confirmed these findings, with OTA-VM digests showing significantly lower ROS levels compared to OTA digests, resulting in a 3.7-fold decrease. Thus, bilberries exhibit high potential as a functional ingredient, demonstrating protection in OTA mitigation effects. Full article

Background: Breast cancer represents one of the leading causes of death among women. Surgery can be effective, but once breast cancer has metastasized, it becomes extremely difficult to treat. Conventional therapies are associated with substantial toxicity and poor efficacy due to tumor heterogeneity, treatment resistance and disease relapse. Moreover, immune checkpoint blockade appears to offer limited benefit in breast cancer. The poor tumor immunogenicity and the immunosuppressive tumor microenvironment result in scarce T-cell infiltration, leading to a low response rate. Thus, there is considerable interest in the development of improved active immunotherapies capable of sensitizing a patient’s immune system against tumor cells. Methods: We evaluated the in vitro anti-tumor activity of a personalized vaccine based on dendritic cells generated in the presence of interferon (IFN)-α and granulocyte-macrophage colony-stimulating factor (IFN-DC) and loaded with an oxidized lysate from autologous tumor cells expanded as 3D organoid culture maintaining faithful tumor antigenic profiles. Results: Our findings demonstrate that stimulation of breast cancer patients’ lymphocytes with autologous IFN-DC led to efficient Th1-biased response and the generation in vitro of potent cytotoxic activity toward the patients’ own tumor cells. Conclusions: This approach can be potentially applied in association with checkpoint blockade and chemotherapy in the design of new combinatorial therapies for breast cancer. Full article

The aim: to evaluate the incidence of obstructive lesions of the coronary arteries during routine coronary angiography (CAG) before carotid endarterectomy (CEA) and the incidence of perioperative complications. Materials and Methods: We examined a continuous sample of 498 patients before CEA who underwent an invasive evaluation of the coronary bed during CAG. Depending on the hemodynamic significance of coronary artery lesions, the patients were divided into three groups: group I—obstructive coronary artery disease (≥70%) (n = 309, 62.0%); group II—non-obstructive lesions of the coronary arteries (<70%) (n = 118, 23.7%); group III—intact coronary arteries (n = 71, 14.3%). The groups were compared with each other according to the data of the preoperative examination (clinical and anamnestic parameters, laboratory data and results of echocardiography), as well as according to the immediate results of the operation. In the hospital period, adverse cardiovascular events were assessed: death, myocardial infarction (MI), stroke, arrhythmias, atrial fibrillation or flutter (AF/AFL) and combined endpoint. Results: The groups differed significantly in the presence of symptoms of angina pectoris, myocardial infarction and myocardial revascularization procedures in their medical history and in the presence of chronic ischemia of the lower extremities. However, in the group of intact coronary arteries, the symptoms of angina were in 14.1% of patients, and a history of myocardial infarction was in 12.7%. Myocardial revascularization before CEA or simultaneously with it was performed in 43.0% of patients. As a result, it was possible to reduce the number of perioperative cardiac complications (mortality 0.7%, perioperative myocardial infarction 1.96%). Conclusions: The high incidence of obstructive lesions in the coronary arteries in our patients and the minimum number of perioperative complications favor routine CAG before CEA. Full article

Drug discovery historically starts with an established function, either that of compounds or proteins. This can hamper discovery of novel therapeutics. As structure determines function, we hypothesized that unique 3D protein structures constitute primary data that can inform novel discovery. Using a computationally intensive physics-based analytical platform operating at supercomputing speeds, we probed a high-resolution protein X-ray crystallographic library developed by us. For each of the eight identified novel 3D structures, we analyzed binding of sixty million compounds. Top-ranking compounds were acquired and screened for efficacy against breast, prostate, colon, or lung cancer, and for toxicity on normal human bone marrow stem cells, both using eight-day colony formation assays. Effective and non-toxic compounds segregated to two pockets. One compound, Dxr2-017, exhibited selective anti-melanoma activity in the NCI-60 cell line screen. In eight-day assays, Dxr2-017 had an IC50 of 12 nM against melanoma cells, while concentrations over 2100-fold higher had minimal stem cell toxicity. Dxr2-017 induced anoikis, a unique form of programmed cell death in need of targeted therapeutics. Our findings demonstrate proof-of-concept that protein structures represent high-value primary data to support the discovery of novel acting therapeutics. This approach is widely applicable. Full article

The insulin-like growth factor-1 (IGF-1) and insulin axes are upregulated in obesity and obesity-associated esophageal adenocarcinoma (EAC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a contemporary nanotechnology-based paclitaxel (PT) bound to human albumin, ensuring its solubility in water rather than a toxic solvent. Here, we examined the benefits of inhibiting insulin-like growth factor-1 receptor/insulin receptor (IGF-1/IR) signaling and the enhancement of nab-paclitaxel effects by inclusion of the small-molecule inhibitor BMS-754807 using both in vitro and in vivo models of EAC. Using multiple EAC cell lines, BMS-754807 and nab-paclitaxel were evaluated as mono and combination therapies for in vitro effects on cell proliferation, cell death, and cell movement. We then analyzed the in vivo anticancer potency with survival improvement with BMS-754807 and nab-paclitaxel mono and combination therapies. BMS-754807 monotherapy suppressed in vitro cell proliferation and wound healing while increasing apoptosis. BMS-754807, when combined with nab-paclitaxel, enhanced those effects on the inhibition of cell proliferation, increment in cell apoptosis, and inhibition of wound healing. BMS-754807 with nab-paclitaxel produced substantially greater antitumor effects by increasing in vivo apoptosis, leading to increased mice survival compared to those of BMS-754807 or nab-paclitaxel monotherapy. Our outcomes support the use of BMS-754807, alone and in combination with nab-paclitaxel, as an efficient and innovative treatment choice for EAC. Full article

Neonatal hypoxia–ischemia is a major cause of infant death and disability. The only clinically accepted treatment is therapeutic hypothermia; however, cooling is less effective in the most severely encephalopathic infants. Here, we wanted to test the neuroprotective effect of the antioxidant dimethyl fumarate after severe hypoxia–ischemia in neonatal rats. We used a modified Rice–Vannucci model to generate severe hypoxic–ischemic brain damage in day 7 postnatal rats, which were randomized into four experimental groups: Sham, Sham + DMF, non-treated HI, and HI + DMF. We analyzed brain tissue loss, global and regional (cortex and hippocampus) neuropathological scores, white matter injury, and microglial and astroglial reactivity. Compared to non-treated HI animals, HI + DMF pups showed a reduced brain area loss (p = 0.0031), an improved neuropathological score (p = 0.0016), reduced white matter injuries by preserving myelin tracts (p < 0.001), and diminished astroglial (p < 0.001) and microglial (p < 0.01) activation. After severe hypoxia–ischemia in neonatal rats, DMF induced a strong neuroprotective response, reducing cerebral infarction, gray and white matter damage, and astroglial and microglial activation. Although further molecular studies are needed and its translation to human babies would need to evaluate the molecule in piglets or lambs, DMF may be a potential treatment against neonatal encephalopathy. Full article

Despite recent technological progress, carbon monoxide poisoning is still one of the leading causes of domestic and industrial morbidity and mortality. The brain is particularly vulnerable to CO toxicity, and thus the majority of survivors develop delayed movement and cognitive complications. CO binds to haemoglobin in erythrocytes, preventing oxygen delivery to tissues, and additionally inhibits mitochondrial respiration. This renders the effect of CO to be closely related to hypoxia reperfusion injury. Oxygen deprivation, as well as CO poisoning and re-oxygenation, are shown to be able to activate the production of reactive oxygen species and to induce oxidative stress. Here, we review the role of reactive oxygen species production and oxidative stress in the mechanism of neuronal cell death induced by carbon monoxide and re-oxygenation. We discuss possible protective mechanisms used by brain cells with a specific focus on the inhibition of CO-induced ROS production and oxidative stress. Full article

Algal metabolites have been extensively studied as potential anticancer therapeutics. Among them, polysaccharides have attracted much attention because of their beneficial biological effects and safety. In the present research, the chemical characteristics, antitumor, and proapoptotic activities of extracellular polysaccharides (EPS) isolated from a new Bulgarian strain of the green microalga Coelastrella sp. BGV were investigated. A fast and convenient method of precipitation with cold ethanol was used to isolate EPS from the culture medium. The chemical characteristics of the isolated EPS were examined by colorimetric and spectrophotometric analyses, HPSEC-RID and HPLC-UV chromatography, and FT-IR spectroscopy. The results showed that the isolated EPS sample consists of three carbohydrate fractions with different molecular weights (11.5 × 10⁴ Da, 30.7 × 10⁴ Da, and 72.4 × 10⁴ Da, respectively) and contains 7.14 (w/w%) protein. HPLC-UV analysis revealed the presence of galactose and fucose. The total uronic acid content in the sample was 4.5 (w/w%). The IR-FT spectrum of EPS revealed the presence of various functional groups typical of a polysaccharide (or proteoglycan) composed primarily of neutral sugars. The anticancer potential of the obtained EPS was assessed using cell lines with cancerous and non-cancerous origins as in vitro experimental models. The results of the performed MTT assay showed that EPS reduced the viability of the cervical and mammary carcinoma cell lines HeLa and MCF-7, while the control non-cancer cell lines BALB/3T3 and HaCaT were less affected. The HeLa cell line showed the highest sensitivity to the effects of EPS and was therefore used for further studies of its anticancer potential. The ability of EPS to inhibit cancer cell migration was demonstrated by wound-healing (scratch) assay. The cell cycle FACS analysis indicated that the EPS treatment induced significant increases in the sub G1 cell population and decreases of the percentages of cells in the G1, S, and G2-M phases, compared to the control. The fluorescent microscopy studies performed using three different staining methods in combination with Annexin V-FITC flow cytometric analysis clearly demonstrate the ability of EPS to induce cancer cell death via the apoptosis pathway. Moreover, an altered pattern and intensity of the immunocytochemical staining for the apoptosis- and proliferation-related proteins p53, bcl2, and Ki67 was detected in EPS-treated HeLa cancer cells as compared to the untreated controls. The obtained results characterize the new local strain of green microalgae Coelastrella sp. BGV as a producer of EPS with selective antitumor activity and provide an opportunity for further studies of its pharmacological and biotechnological potential. Full article

Cell death is of great significance in maintaining tissue homeostasis and bodily functions. With considerable research coming to the fore, it has been found that programmed cell death presents in multiple modalities in the body, which is not only limited to apoptosis, but also can be divided into autophagy, pyroptosis, ferroptosis, mitotic catastrophe, entosis, netosis, and other ways. Different forms of programmed cell death have disparate or analogous characteristics with each other, and their occurrence is accompanied by multiple signal transduction and the role of a myriad of regulatory factors. In recent years, scholars across the world have carried out considerable in-depth research on programmed cell death, and new forms of cell death are being discovered continually. Concomitantly, the mechanisms of intricate signaling pathways and regulators have been discovered. More critically, cancer cells tend to choose distinct ways to evade cell death, and different tumors adapt to different manners of death. Therefore, targeting the cell death network has been regarded as an effective tumor treatment strategy for a long time. The objective of our paper is to review the signaling pathways and gene regulation in several typical types of programmed cell death and their correlation with cancer. Full article

This article will use syndemic theory to identify and analyze overlapping health and social conditions, focusing specifically on how gender-based violence is systemically interconnected with contemporary public health issues. The overdose death crisis that continues to afflict Canadian populations is not an isolated health issue. Across Canada, it is intertwined with mental health, HIV/AIDS, COVID-19 and structural violence—the chronic and systemic disadvantages affecting those living in poverty and oppressive circumstances. Opioid use is an often-avoidant coping strategy for many experiencing the effects of trauma, relentless fear, pain, ill health and social exclusion. In particular, Indigenous and non-Indigenous women’s experiences with opioid addiction are entangled with encounters with gender based-violence, poverty and chronic ailments within structurally imposed processes and stressors shaped by a history of colonialism, ruptured lifeways and Western ways of knowing and doing, leading to disproportionate harms and occurrences of illness. While biomedical models of comorbidity and mortality approach substance misuse, gender-based violence and major infectious diseases such as HIV/AIDS and COVID-19 as distinct yet compounding realities, this article argues that these conditions are synergistically interrelated via the critical/reflexive lens of syndemic frameworks. Through secondary research using academic, media and policy sources from the past decade in Canada, complemented by prior ethnographic research, the synergistic connections among opioid addiction, gender-based violence and the effects of the COVID pandemic on diverse women will be shown to be driven by socio-structural determinants of health including poverty, intergenerational trauma, the legacy of colonialism and Western optics. Together, they embody a contemporary Canadian syndemic necessitating coordinated responses. Full article

Chemotherapy has been widely applied in oncotherapy. However, the development of multidrug resistance (MDR) has diminished the effectiveness of anticancer drugs against tumor cells. Such resistance often results in tumor recurrence, metastasis, and patient death. Fortunately, nanoparticle-based drug delivery systems provide a promising strategy by codelivery of multiple drugs and MDR reversal agents and the skillful, flexible, smart modification of drug targets. Such systems have demonstrated the ability to bypass the ABC transporter biological efflux mechanisms due to drug resistance. Hence, how to deliver drugs and exert potential antitumor effects have been successfully explored, applied, and developed. Furthermore, to overcome multidrug resistance, nanoparticle-based systems have been developed due to their good therapeutic effect, low side effects, and high tumor metastasis inhibition. In view of this, we systematically discuss the molecular mechanisms and therapeutic strategies of MDR from nanotherapeutics. Finally, we summarize intriguing ideas and future trends for further research in overcoming MDR. Full article

Since 2020, southern Brazil’s Rio Grande do Sul (RS) State has been affected by extreme precipitation episodes caused by different atmospheric systems. However, the most extreme was registered between the end of April and the beginning of May 2024. This extreme precipitation caused floods in most parts of the state, affecting 2,398,255 people and leading to 183 deaths and 27 missing persons. Due to the severity of this episode, we need to understand its drivers. In this context, the main objective of this study is a multi-scale analysis of the extreme precipitation between 26 April and 5 May, i.e., an analysis of the large-scale patterns of the atmosphere, a description of the synoptic environment, and an analysis of the mesoscale viewpoint (cloud-top features and lightning). Data from different sources (reanalysis, satellite, radar, and pluviometers) were used in this study, and different methods were applied. The National Center for Monitoring and Early Warning of Natural Disasters (CEMADEN) registered accumulated rainfall above 400 mm between 26 April and 5 May using 27 pluviometers located in the central-northern part of RS. The monthly volumes reached 667 mm and 803 mm, respectively, for April and May 2024, against a climatological average of 151 mm and 137 mm for these months. The maximum precipitation recorded was 300 mm in a single day on 30 April 2024. From a large-scale point of view, an anomalous heat source in the western Indian Ocean triggered a Rossby wave that contributed to a barotropic anticyclonic anomalous circulation over mid-southeastern Brazil. While the precipitant systems were inhibited over this region (the synoptic view), the anomalous stronger subtropical jet southward of the anticyclonic circulation caused uplift over RS State and, consequently, conditions leading to mesoscale convective system (MCS) development. In addition, the low-level jet east of the Andes transported warm and moist air to southern Brazil, which also interacted with two cold fronts that reached RS during the 10-day period, helping to establish the precipitation. Severe deep MCSs (with a cloud-top temperature lower than −80 °C) were responsible for a high lightning rate (above 10 flashes km⁻² in 10 days) and accumulated precipitation (above 600 mm in 10 days), as observed by satellite measurements. This high volume of rainfall caused an increase in soil moisture, which exceeded a volume fraction of 0.55, making water infiltration into the soil difficult and, consequently, favoring flood occurrence. Full article

Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell’s survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative phosphorylation, which provides essential energy for cellular functions, mitochondria also participate in other metabolic processes within the cell, such as the electron transport chain, citric acid cycle, and β-oxidation of fatty acids. Furthermore, mitochondria regulate the production and elimination of ROS, the synthesis of nucleotides and amino acids, the balance of calcium ions, and the process of cell death. Therefore, it is widely accepted that mitochondrial dysfunction is a factor that causes or contributes to the development and advancement of various diseases. These include common systemic diseases, such as aging, diabetes, Parkinson’s disease, and cancer, as well as rare metabolic disorders, like Kearns–Sayre syndrome, Leigh disease, and mitochondrial myopathy. This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities. Additionally, it provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health. Full article

The herbicide paraquat (PQ) is responsible for a significant number of fatalities resulting from self-poisoning. Nevertheless, only a limited number of comprehensive studies focusing on fatal PQ poisoning, which include examination of autopsy findings, histopathology, and quantitative analysis of post-mortem samples, have been published. This study aimed to evaluate autopsy findings, histopathology, and quantitative analysis of PQ in post-mortem human serum samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS), a simple, sensitive, and specific method. Autopsies were performed on all deaths due to PQ poisoning, and serum samples were sent to the toxicology laboratory for chemical analysis. The method was successfully applied to seven human serum samples, and the results indicate its reliability for detecting PQ. The study reports fatal serum PQ levels ranging from 0.5 to 372.0 µg/mL. The comprehensive data presented in this study can be useful for further research and practical applications. Full article