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There has been a surge of interest in recent years in understanding the intricate mechanisms underlying cancer progression and treatment resistance. One molecule that has recently emerged in these mechanisms is MUC13 mucin, a transmembrane glycoprotein. Researchers have begun to unravel the molecular complexity of MUC13 and its impact on cancer biology. Studies have shown that MUC13 overexpression can disrupt normal cellular polarity, leading to the acquisition of malignant traits. Furthermore, MUC13 has been associated with increased cancer plasticity, allowing cells to undergo epithelial-mesenchymal transition (EMT) and metastasize. Notably, MUC13 has also been implicated in the development of chemoresistance, rendering cancer cells less responsive to traditional treatment options. Understanding the precise role of MUC13 in cellular plasticity, and chemoresistance could pave the way for the development of targeted therapies to combat cancer progression and enhance treatment efficacy.
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Plasticidad de la Célula , Resistencia a Antineoplásicos , Mucinas , Neoplasias , Humanos , Neoplasias/patología , Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Mucinas/metabolismo , Animales , Transición Epitelial-MesenquimalRESUMEN
Tumor heterogeneity is a predominant feature of hepatocellular carcinoma (HCC) that plays a crucial role in chemoresistance and limits the efficacy of available chemo/immunotherapy regimens. Thus, a better understanding regarding the molecular determinants of tumor heterogeneity will help in developing newer strategies for effective HCC management. Chemokines, a sub-family of cytokines are one of the key molecular determinants of tumor heterogeneity in HCC and are involved in cell survival, growth, migration, and angiogenesis. Herein, we provide a panoramic insight into the role of chemokines in HCC heterogeneity at genetic, epigenetic, metabolic, immune cell composition, and tumor microenvironment levels and its impact on clinical outcomes. Interestingly, our in-silico analysis data showed that expression of chemokine receptors impacts infiltration of various immune cell populations into the liver tumor and leads to heterogeneity. Thus, it is evident that aberrant chemokines clouding impacts HCC tumor heterogeneity and understanding this phenomenon in depth could be harnessed for the development of personalized medicine strategies in future.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/metabolismo , Quimiocinas/metabolismo , Microambiente Tumoral/genética , Neovascularización PatológicaRESUMEN
Piperlongumine (PL, piplartine) is an alkaloid derived from the Piper longum L. (long pepper) roots. Originally discovered in 1961, the biological activities of this molecule against some cancer types was reported during the last decade. Whether PL can synergize with doxorubicin and the underlying mechanism in breast cancer remains elusive. Herein, we report the activities of PL in numerous breast cancer cell lines. PL reduced the migration and colony formation by cancer cells. An enhancement in the sub-G1 population, reduction in the mitochondrial membrane potential, chromatin condensation, DNA laddering and suppression in the cell survival proteins was observed by the alkaloid. Further, PL induced ROS generation in breast cancer cells. While TNF-α induced p65 nuclear translocation, PL suppressed the translocation in cancer cells. The expression of lncRNAs such as MEG3, GAS5 and H19 were also modulated by the alkaloid. The molecular docking studies revealed that PL can interact with both p65 and p50 subunits. PL reduced the glucose import and altered the pH of the medium towards the alkaline side. PL also suppressed the expression of glucose and lactate transporter in breast cancer cells. In tumor bearing mouse model, PL was found to synergize with doxorubicin and reduced the size, volume and weight of the tumor. Overall, the effects of doxorubicin in cancer cells are enhanced by PL. The modulation of glucose import, NF-κB activation and lncRNAs expression may have contributory role for the activities of PL in breast cancer.
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Alcaloides , Antineoplásicos , Neoplasias de la Mama , Dioxolanos , Piper , ARN Largo no Codificante , Alcaloides/farmacología , Alcaloides/uso terapéutico , Animales , Antineoplásicos/farmacología , Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Línea Celular Tumoral , Dioxolanos/farmacología , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Femenino , Glucosa/farmacología , Humanos , Ratones , Simulación del Acoplamiento Molecular , FN-kappa B/genética , FN-kappa B/metabolismo , Piper/química , ARN Largo no Codificante/genética , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Stem cells are very promising for the treatment of a plethora of human diseases. Numerous clinical studies have been conducted to assess the safety and efficacy of various stem cell types. Factors that ensure successful therapeutic outcomes in patients are cell-based parameters such as source, viability, and number, as well as frequency and timing of intervention and disease stage. Stem cell administration routes should be appropriately chosen as these can affect homing and engraftment of the cells and hence reduce therapeutic effects, or compromise safety, resulting in serious adverse events. In this chapter, we will describe the use of stem cells in organ repair and regeneration, in particular, the liver and the available routes of cell delivery in the clinic for end-stage liver diseases. Factors affecting homing and engraftment of stem cells for each administration route will be discussed.
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The head and neck squamous cell carcinoma (HNSCC) constitute about 90% of all head and neck cancers. HNSCC falls in the top 10 cancers in men globally. Epoxyazadiradione (EPA) and Azadiradione (AZA) are the limonoids derived from the medicinal plant Azadirachta indica (popularly known as Neem). Whether or not the limonoids exhibit activities against HNSCC and the associated mechanism remains elusive. Herein, we demonstrate that EPA exhibits stronger activity in HNSCC in comparison to AZA. The limonoids obeyed the Lipinski's rule of 5. EPA exhibited activities in a variety of HNSCC lines like suppression of the proliferation and the induction of apoptosis. The limonoid suppressed the level of proteins associated with anti-apoptosis (survivin, Bcl-2, Bcl-xL), proliferation (cyclin D1), and invasion (MMP-9). Further, the expression of proapoptotic Bax and caspase-9 cleavage was induced by the limonoid. Exposure of EPA induced reactive oxygen species (ROS) generation in the FaDu cells. N-acetyl-L-cysteine (ROS scavenger) abrogated the down-regulation of tumorigenic proteins caused by EPA exposure. EPA induced NOX-5 while suppressing the expression of programmed death-ligand 1 (PD-L1). Further, hydrogen peroxide induced NF-κB-p65 nuclear translocation and EPA inhibited the translocation. Finally, EPA modulated the expression of lncRNAs in HNSCC lines. Overall, these results have shown that EPA exhibit activities against HNSCC by targeting multiple cancer related signalling molecules. Currently, we are evaluating the efficacy of this molecule in mice models.
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Antígeno B7-H1/genética , Limoninas/farmacología , NADPH Oxidasa 5/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Factor de Transcripción ReIA/genética , Animales , Apoptosis/efectos de los fármacos , Azadirachta/química , Proliferación Celular/efectos de los fármacos , Ciclina D1/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Metaloproteinasa 9 de la Matriz/genética , Ratones , Proteínas Proto-Oncogénicas c-bcl-2/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Survivin/genéticaRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic, an infection caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), has led to more than 771,000 deaths worldwide. Tobacco smoking is a major known risk factor for severe illness and even death from many respiratory infections. The effects of smoking on COVID-19 are currently controversial. Here, we provide an overview of the current knowledge on the effects of smoking on the clinical manifestations, disease progression, inflammatory responses, immunopathogenesis, racial ethnic disparities, and incidence of COVID-19. This review also documents future directions of smoking related research in COVID-19. The current epidemiological finding suggests that active smoking is associated with an increased severity of disease and death in hospitalized COVID-19 patients. Smoking can upregulate the angiotensin-converting enzyme-2 (ACE-2) receptor utilized by SARS-CoV-2 to enter the host cell and activate a 'cytokine storm' which can lead to worsen outcomes in COVID-19 patients. This receptor can also act as a potential therapeutic target for COVID-19 and other infectious diseases. The COVID-19 pandemic sheds light on a legacy of inequalities regarding gender, racial, and ethnic health disparities associated with active smoking, thus, smoking cessation may help in improving outcomes. In addition, to flatten the COVID-19 curve, staying indoors, avoiding unnecessary social contact, and bolstering the immune defense system by maintaining a healthy diet/living are highly desirable.
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Infecciones por Coronavirus/epidemiología , Neumonía Viral/epidemiología , Fumar/epidemiología , COVID-19 , Humanos , PandemiasRESUMEN
The role of niacin's metabolite, nicotinamide adenine dinucleotide (NAD), in DNA repair via base-excision repair pathway is well documented. We evaluated if niacin deficiency results in genetic instability in normal human fetal lung fibroblasts (MRC-5), and further, does it leads to enhanced accumulation of cigarette smoke-induced genetic damage? MRC-5 cells were grown discretely in niacin-proficient/deficient media, and exposed to nicotine-derived nitrosamine ketone (NNK, a cigarette smoke carcinogen). Niacin deficiency abated the NAD polymerization, augmented the spontaneous induction of micronuclei (MN) and chromosomal aberrations (CA) and raised the expression of 10 genes and suppressed 12 genes involved in different biological functions. NNK exposure resulted in genetic damage as measured by the induction of MN and CA in cells grown in niacin-proficient medium, but the damage became practically marked when niacin-deficient cells were exposed to NNK. NNK exposure raised the expression of 16 genes and suppressed the expression of 56 genes in cells grown in niacin-proficient medium. NNK exposure to niacin-deficient cells raised the expression of eight genes including genes crucial in promoting cancer such as FGFR3 and DUSP1 and suppressed the expression of 33 genes, including genes crucial in preventing the onset and progression of cancer like RASSF2, JUP, and IL24, in comparison with the cells grown in niacin-proficient medium. Overall, niacin deficiency interferes with the DNA damage repair process induced by chemical carcinogens like NNK, and niacin-deficient population are at the higher risk of genetic instability caused by cigarette smoke carcinogen NNK.
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Neoplasias/genética , Niacina/deficiencia , Fumadores , Carcinógenos/farmacología , Línea Celular , Aberraciones Cromosómicas/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Investigación Fetal , Fibroblastos/fisiología , Expresión Génica , Humanos , Pulmón/citología , Micronúcleos con Defecto Cromosómico/inducido químicamente , Pruebas de Micronúcleos , NAD/metabolismo , Nitrosaminas/farmacología , PolimerizacionRESUMEN
The immune signalling genes during the challenge of bovine macrophages with bacterial products derived from tuberculosis causing bacteria in cattle were investigated in the present study. An in-vitro cell culture model of bovine monocyte-derived macrophages were challenged to Mycobacterium bovis. Macrophages from healthy and already infected animals can both be fully activated during M. bovis infection. Analysis of mRNA abundance in peripheral blood mononuclear cells from M. bovis infected and non-infected cattle were performed as a controls. Cells of treatment were challenged after six days for six hours incubation at 37 °C, with 5% CO2, to total RNA was extracted then cDNA labelling, hybridization and scanning for microarray methods have been developed for microarray based immune related gene expression analysis. The differential expressions twenty genes (IL1, CCL3, CXCR4, TNF, TLR2, IL12, CSF3, CCR5, CCR3, MAPT, NFKB1, CCL4, IL6, IL2, IL23A, CCL20, IL8, CXCL8, TRIP10, CXCL2 and IL1B) implicated in M. bovis response were examined Agilent Bovine_GXP_8 × 60 K microarray platform. Cells of treatment were challenged after six days for six hours incubation then pathways analysis of Toll like receptor and Chemokine signalling pathway study of responsible genes in bovine tuberculosis. The PBMC from M. bovis infected cattle exhibit different transcriptional profiles compared with PBMC from healthy control animals in response to M. bovis antigen stimulation, providing evidence of a novel genes expression program due to M. bovis exposure. It will guide future studies, regarding the complex macrophage specific signalling pathways stimulated upon phagocytosis of M. bovis and role of signalling pathways in creating the host immune response to cattle tuberculosis.
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Regulación de la Expresión Génica/inmunología , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Mycobacterium bovis/inmunología , Tuberculosis Bovina/inmunología , Animales , Bovinos , Células Cultivadas , Macrófagos/microbiología , Fagocitosis/genética , ARN Mensajero/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Tuberculosis Bovina/microbiologíaRESUMEN
Nanotechnology is a promptly growing field in this century, and it have been extensively used in several solicitations. Reactive oxygen species (ROS) generation is one of the important mechanism of action of nanoparticles. The excess ROS generation can induce oxidative stress, so the cells are unable to sustain the normal biological redox-regulated tasks. The high oxidative stress and ROS formation condition, damage the biological macromolecules, cell signaling pathways and finally leads to cell death or cancer initiation. The objective of the present study is to reveal the effects of TiO2 nanoparticle on co-culture system. The cell viability, oxidative stress and apoptosis were evaluated in monolayer and co-culture 3T3-L1 cells after the exposure of TiO2. Our results indicated that TiO2 significantly induces the reactive oxygen species (ROS), lipid peroxidation and decrease in the level of glutathione. Additionally, real-time PCR data analysis shown an increased in the expression of p53, Bax, caspase-9, caspase-3 and decreased the level of Bcl-2, by this means specifying that apoptosis induced by TiO2 NPs occurs via the caspase-dependent pathway. This study analytically shows that oxidative stress is the fundamental mechanism by which TiO2 causes apoptosis in a co-culture system even at very low concentrations. In the future, the use of such nanoparticles should be cautiously scrutinized.
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Apoptosis/efectos de los fármacos , Nanopartículas del Metal , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno , Titanio/química , Animales , Supervivencia Celular , Ratones , Titanio/farmacologíaRESUMEN
PURPOSE: The linkage of human T-cell leukemia virus type 1 (HTLV-1) to fatal diseases is a well known fact for many years. However, there has been no significant progress in the field of the treatment that can lead to the development of a successful vaccine. Furthermore, there are no means of assessing the risk of disease and its prognosis in the infected people. METHODS: The current study has taken the cognizance of the importance of host's immune response in reducing the risk of infectious diseases to carry out immunoinformatics driven epitope screening strategy of vaccine candidates against HTLV-1. In this study, a genetic variability and HLA distribution analysis among the documented HTLV-1 genotypes I, II, III, IV, V & VI was performed to ensure the coverage of the vast majority of population, where vaccine would be employed. The meticulous screening of effective dominant immunogens was done with the help of ABCPred and Immune Epitope Database. RESULTS: The results showed that the identified epitopes might be protective immunogens with high conservancy and potential of inducing both protective neutralizing antibodies and T-cell responses. The peptides "PSQLPPTAPPLLPHSNLDHI", "PCPNLVAYSSYHATY", and "YHATYSLYLF", were 100% conserved among different isolates from far and wide separated countries, suggesting negligible antigenic drift in HTLV-1. CONCLUSIONS: Overall, the mentioned epitopes are soluble, non-toxic suitable candidates for the development of vaccine against HTLV-1 and warrant further investigation and experimental validation.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígenos HLA/inmunología , Virus Linfotrópico T Tipo 1 Humano/inmunología , Secuencia de Aminoácidos , Anticuerpos Neutralizantes/inmunología , Epítopos/inmunología , Infecciones por HTLV-I/inmunología , Infecciones por HTLV-I/virología , Humanos , Inmunidad HumoralRESUMEN
We examined the interaction of polycyclic hydrocarbons (PAHs) like benzo-α-pyrene (BaP), chrysene, and their metabolites 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene,9,10-oxide (BPDE) and chrysene 1,2-diol-3,4-epoxide-2 (CDE), with the enzymes involved in DNA repair. We investigated interaction of 120 enzymes with PAHs and screened out 40 probable targets among DNA repair enzymes, on the basis of higher binding energy than positive control. Out of which, 20 enzymes lose their function in the presence of BaP, chrysene, and their metabolites, which may fetter DNA repair pathways resulting in damage accumulation and finally leading to cancer formation. We propose the use of nanoparticles as a guardian against the PAH's induced toxicity. PAHs enter the cell via aryl hydrocarbon receptor (AHR). TiO2 NP showed a much higher docking score with AHR (12,074) as compared with BaP and chrysene with AHR (4,600 and 4,186, respectively), indicating a preferential binding of TiO2 NP with the AHR. Further, docking of BaP and chrysene with the TiO2 NP bound AHR complex revealed their strong adsorption on TiO2 NP itself, and not on their original binding site (at AHR). TiO2 NPs thereby prevent the entry of PAHs into the cell via AHR and hence protect cells against the deleterious effects induced by PAHs.
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Benzopirenos/toxicidad , Crisenos/toxicidad , Biología Computacional , Reparación del ADN/efectos de los fármacos , Nanopartículas , Titanio/química , Titanio/farmacología , Enzimas Reparadoras del ADN/química , Enzimas Reparadoras del ADN/metabolismo , Humanos , Modelos Moleculares , Conformación Molecular , Simulación del Acoplamiento Molecular , Conformación Proteica , Titanio/metabolismoRESUMEN
ims: The aim of this study was to evaluate the combined and comparative efficacy of Caffeic acid phenethyl ester (CAPE) and curcumin in breast cancer. BACKGROUND: CAPE and curcumin are a class of phenolics. While curcumin is obtained from turmeric, CAPE is found in Baccharis sarothroides and Populus deltoides. Both agents are reported to produce activities in some cancer types. The combined and comparative effects of the two agents in breast cancer have not yet reported. OBJECTIVE: We evaluated the potential of CAPE and curcumin in both in vitro and in vivo breast cancer models. METHODS: Human breast cancer cell lines, MDA-MB-231 and MCF-7, were exposed to CAPE and curcumin, followed by functional assays such as cell cytotoxicity, cell proliferation and colony formation, cell cycle, mitochondrial membrane potential, apoptosis, and monodansylcadaverine (MDC) staining for autophagy. Computational analyses and mouse models were also used. RESULTS: Employing computational analyses, both agents were found to exhibit drug-like properties. Both molecules interacted with the key molecules of the NF-κB pathway. CAPE and curcumin inhibited cell proliferation, colony formation, and invasion, triggering apoptosis in breast cancer cells. CAPE was found to be more effective than curcumin. Two agents working together were more effective than each agent working alone. Both agents suppressed the expression of survivin, Bcl-xL and GLUT-1. The level of cleaved PARP was increased by both agents. Both phenolics observed an induction in ROS generation. Further, both molecules triggered a dissipation in mitochondrial membrane potential. In mice models implanted with Ehrlich-Lettre ascites carcinoma (EAC) cells, both drugs inhibited the growth of the tumour. The phenolics also modulated the metabolic parameters in tumour-bearing mice. CONCLUSION: The observations suggest that the combination of curcumin plus CAPE may be better in comparison to individual molecules. Other: The study opens a window for analysing the efficacy of the combination of CAPE and curcumin in animal studies. This will provide a basis for examining the combined efficacy of two agents in a clinical trial.
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BACKGROUND: The trends of pancreatic cancer (PanCa) incidence and mortality are on rising pattern, and it will be a second leading cause of cancer related deaths by 2030. Pancreatic ductal adenocarcinoma (PDAC), major form of PanCa, exhibits a grim prognosis as mortality rate is very close to the incidence rate, due to lack of early detection methods and effective therapeutic regimen. Considering this alarming unmet clinic need, our team has identified a novel oncogenic protein, carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7), that can be useful for spotting early events of PDAC. METHODOLOGY: This study includes bioinformatics pre-screening using publicly available cancer databases followed by molecular biology techniques in PDAC progressive cell line panel and human tissues to evaluate CEACAM7 expression in early events of pancreatic cancer. RESULTS: PanCa gene and protein expression analysis demonstrated the significantly higher expression of CEACAM7 in PDAC, compared to other cancers and normal pancreas. Overall survival analysis demonstrated an association between the higher expression of CEACAM7 and poor patients' prognosis with high hazard ratio. Additionally, in a performance comparison analysis CEACAM7 outperformed S100A4 in relation to PDAC. We also observed an increase of CEACAM7 in PDAC cell line panel model. However, poorly differentiated, and normal cell lines did not show any expression. Human tissue analysis also strengthened our data by showing strong and positive IHC staining in early-stage tumors. CONCLUSION: Our observations clearly cite that CEACAM7 can serve as a potential early diagnostic and/or prognostic marker of PDAC and may also potentiate the sensitivity of the existing biomarker panel of PDAC. However, further studies are warranted to determine its clinical significance.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Pronóstico , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Antígeno Carcinoembrionario , Proteínas Ligadas a GPI/genéticaRESUMEN
Prohibitin (PHB) is a pleiotropic molecule with a variety of known functions and subcellular locations. PHB's function in breast cancer is poorly understood. Herein, we report that PHB is expressed in cancer types of diverse origin including breast cancer. The cancer patients with changes in PHB were reported to have significantly reduced 'overall survival' in comparison to the cases without alterations in PHB. The expression of PHB was increased by H2O2 and also by Moringin (MG), which is an isothiocyanate derived from the seeds of Moringa oleifera. MG interacted with PHB, DRP1, and SLP2 and inhibited the growth of MCF-7 and MDAMB-231 cells. The isothiocyanate triggered apoptosis in breast cancer cells as revealed by AO/PI assay, phosphatidylserine externalization, cell cycle analysis and DAPI staining. MG induced proapoptotic proteins expression such as cytochrome c, p53, and cleaved caspase-7. Further, cell survival proteins such as survivin, Bcl-2, and Bcl-xL were suppressed. A depolarization of membrane potential suggested that the apoptosis was triggered through mitochondria. The isothiocyanate suppressed the cancer cell migration and interacted with NF-κB subunits. MG suppressed p65 nuclear translocation induced by TNF-α. The reactive oxygen species generation was also induced by the isothiocyanate in breast cancer cells. MG also modulated the expression of lncRNAs. Collectively, the functions of PHB in breast cancer growth is evident from this study. The activities of MG against breast cancer might result from its ability to modulate multiple cancer-related targets.
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Apoptosis , Neoplasias de la Mama , Isotiocianatos , Prohibitinas , Transducción de Señal , Humanos , Isotiocianatos/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteínas Represoras/metabolismo , Línea Celular Tumoral , Células MCF-7 , Movimiento Celular/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/metabolismo , FN-kappa B/metabolismo , Proliferación Celular/efectos de los fármacosRESUMEN
Gastrointestinal (GI) cancers comprise of cancers that affect the digestive system and its accessory organs. The late detection and poor prognosis of GI cancer emphasizes the importance of identifying reliable and precise biomarkers for early diagnosis and prediction of prognosis. The membrane-bound glycoprotein dipeptidyl-peptidase 4 (DPP4), also known as CD26, is ubiquitously expressed and has a wide spectrum of biological roles. The role of DPP4/CD26 in tumor progression in different types of cancers remains elusive. However, the link between DPP4 and tumor-infiltrating cells, as well as its prognostic significance in malignancies, still require further investigation. This study was intended to elucidate the correlation of DPP4 expression and survival along with prognosis, followed by its associated enriched molecular pathways and immune cell marker levels in upper GI cancers. Results demonstrated a strong correlation between increased DPP4 expression and a worse prognosis in esophageal and gastric cancer and the co-expressed common genes with DPP4 were associated with crucial molecular pathways involved in tumorigenesis. Additionally, DPP4 was shown to be significantly linked to several immune infiltrating cell marker genes, including Macrophages (M1, M2 and Tumor Associated Macrophages), neutrophils, Treg, T-cell exhaustion, Th1 and Th2. Overall, our findings suggest that DPP4 may serve as a substantial prognostic biomarker, a possible therapeutic target, as well as it can play a critical role in the regulation of immune cell invasion in patients with gastroesophageal (esophageal, gastroesophageal junction and gastric) cancer. KEY WORDS: DPP4, integrated analysis, GI cancer, gastroesophageal cancer, gastroesophageal junction, prognosis.
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Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Macrófagos/metabolismoRESUMEN
The post-pandemic era following the global spread of the SARS-CoV-2 virus has brought about persistent concerns regarding recurring coinfections. While significant strides in genome mapping, diagnostics, and vaccine development have controlled the pandemic and reduced fatalities, ongoing virus mutations necessitate a deeper exploration of the interplay between SARS-CoV-2 mutations and the host's immune response. Various vaccines, including RNA-based ones like Pfizer and Moderna, viral vector vaccines like Johnson & Johnson and AstraZeneca, and protein subunit vaccines like Novavax, have played critical roles in mitigating the impact of COVID-19. Understanding their strengths and limitations is crucial for tailoring future vaccines to specific variants and individual needs. The intricate relationship between SARS-CoV-2 mutations and the immune response remains a focus of intense research, providing insights into personalized treatment strategies and long-term effects like long-COVID. This article offers an overview of the post-pandemic landscape, highlighting emerging variants, summarizing vaccine platforms, and delving into immunological responses and the phenomenon of long-COVID. By presenting clinical findings, it aims to contribute to the ongoing understanding of COVID-19's progression in the aftermath of the pandemic.
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COVID-19 , Coinfección , Humanos , SARS-CoV-2 , Síndrome Post Agudo de COVID-19 , Pandemias , Vacunas de Subunidades ProteicasRESUMEN
The application of extracellular vesicles, particularly exosomes (EXs), is rapidly expanding in the field of medicine, owing to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we show that exosomes (EXs) derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.
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In cancer combination therapy, a multimodal delivery vector is used to improve the bioavailability of multiple anti-cancer hydrophobic drugs. Further, targeted delivery of therapeutics along with simultaneous monitoring of the drug release at the tumor site without normal organ toxicity is an emerging and effective strategy for cancer treatment. However, the lack of a smart nano-delivery system limits the application of this therapeutic strategy. To overcome this issue, a PEGylated dual drug, conjugated amphiphilic polymer (CPT-S-S-PEG-CUR), has been successfully synthesized by conjugating two hydrophobic fluorescent anti-cancer drugs, curcumin (CUR) and camptothecin (CPT), through an ester and a redox-sensitive disulfide (-S-S-) linkage, respectively, with a PEG chain via in situ two-step reactions. CPT-S-S-PEG-CUR is spontaneously self-assembled in the presence of tannic acid (TA, a physical crosslinker) into anionic, comparatively smaller-sized (~100 nm), stable nano-assemblies in water in comparison to only polymer due to stronger H-bond formation between polymer and TA. Further, due to the spectral overlap between CPT and CUR and a stable, smaller nano-assembly formation by the pro-drug polymer in water in presence of TA, a successful Fluorescence Resonance Energy Transfer (FRET) signal was generated between the conjugated CPT (FRET donor) and conjugated CUR (FRET acceptor). Interestingly, these stable nano-assemblies showed a preferential breakdown and release of CPT in a tumor-relevant redox environment (in the presence of 50 mM glutathione), leading to the disappearance of the FRET signal. These nano-assemblies exhibited a successful cellular uptake by the cancer cells and an enhanced antiproliferative effect in comparison to the individual drugs in cancer cells (AsPC1 and SW480). Such promising in vitro results with a novel redox-responsive, dual-drug conjugated, FRET pair-based nanosized multimodal delivery vector can be highly useful as an advanced theranostic system towards effective cancer treatment.
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BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive and terminal neurodegenerative disorder. Mitochondrial dysfunction, imbalance of cellular bioenergetics, electron chain transportation and calcium homeostasis are deeply associated with the progression of this disease. Impaired mitochondrial functions are crucial in rapid neurodegeneration. The mitochondria of ALS patients are associated with deregulated Ca2+ homeostasis and elevated levels of reactive oxygen species (ROS), leading to oxidative stress. Overload of mitochondrial calcium and ROS production leads to glutamatereceptor mediated neurotoxicity. This implies mitochondria are an attractive therapeutic target. OBJECTIVE: The aim of this review is to brief the latest developments in the understanding of mitochondrial pathogenesis in ALS and emphasize the restorative capacity of therapeutic candidates. RESULTS: In ALS, mitochondrial dysfunction is a well-known phenomenon. Various therapies targeted towards mitochondrial dysfunction aim at decreasing ROS generation, increasing mitochondrial biogenesis, and inhibiting apoptotic pathways. Some of the therapies briefed in this review may be categorized as synthetic, natural compounds, genetic materials, and cellular therapies. CONCLUSION: The overarching goals of mitochondrial therapies in ALS are to benefit ALS patients by slowing down the disease progression and prolonging overall survival. Despite various therapeutic approaches, there are many hurdles in the development of a successful therapy due to the multifaceted nature of mitochondrial dysfunction and ALS progression. Intensive research is required to precisely elucidate the molecular pathways involved in the progression of mitochondrial dysfunctions that ultimately lead to ALS. Because of the multifactorial nature of ALS, a combination therapy approach may hold the key to cure and treat ALS in the future.