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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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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
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
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
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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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
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
Pancreatic cancer (PanCa) is one of the most aggressive forms of cancer and its incidence rate is continuously increasing every year. It is expected that by 2030, PanCa will become the 2nd leading cause of cancer-related deaths in the United States due to the lack of early diagnosis and extremely poor survival. Despite great advancements in biomedical research, there are very limited early diagnostic modalities available for the early detection of PanCa. Thus, understanding of disease biology and identification of newer diagnostic and therapeutic modalities are high priority. Herein, we have utilized high dimensional omics data along with some wet laboratory experiments to decipher the expression level of hormone receptor interactor 13 (TRIP13) in various pathological staging including functional enrichment analysis. The functional enrichment analyses specifically suggest that TRIP13 and its related oncogenic network genes are involved in very important patho-physiological pathways. These analyses are supported by qPCR, immunoblotting and IHC analysis. Based on our study we proposed TRIP13 as a novel molecular target for PanCa diagnosis and therapeutic interventions. Overall, we have demonstrated a crucial role of TRIP13 in pathogenic events and progression of PanCa through applied integrated computational biology approaches.
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Big data analysis holds a considerable influence on several aspects of biomedical health science. It permits healthcare providers to gain insights from large and complex datasets, leading to improvements in the understanding, diagnosis, medication, and restraint of pathological conditions including cancer. The incidences of pancreatic cancer (PanCa) are sharply rising, and it will become the second leading cause of cancer related deaths by 2030. Various traditional biomarkers are currently in use but are not optimal in sensitivity and specificity. Herein, we determine the role of a new transmembrane glycoprotein, MUC13, as a potential biomarker of pancreatic ductal adenocarcinoma (PDAC) by using integrative big data mining and transcriptomic approaches. This study is helpful to identify and appropriately segment the data related to MUC13, which are scattered in various data sets. The assembling of the meaningful data, representation strategy was used to investigate the MUC13 associated information for the better understanding regarding its structural, expression profiling, genomic variants, phosphorylation motifs, and functional enrichment pathways. For further in-depth investigation, we have adopted several popular transcriptomic methods like DEGseq2, coding and non-coding transcript, single cell seq analysis, and functional enrichment analysis. All these analyzes suggest the presence of three nonsense MUC13 genomic transcripts, two protein transcripts, short MUC13 (s-MUC13, non-tumorigenic or ntMUC13), and long MUC13 (L-MUC13, tumorigenic or tMUC13), several important phosphorylation sites in tMUC13. Altogether, this data confirms that importance of tMUC13 as a potential biomarker, therapeutic target of PanCa, and its significance in pancreatic pathobiology.
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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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Indocyanine green (ICG) is one of the FDA-approved near infra-red fluorescent (NIRF) probes for cancer imaging and image-guided surgery in the clinical setting. However, the limitations of ICG include poor photostability, high concentration toxicity, short circulation time, and poor cancer cell specificity. To overcome these hurdles, we engineered a nanoconstruct composed of poly (vinyl pyrrolidone) (PVP)-indocyanine green that is cloaked self-assembled with tannic acid (termed as indocyanine green-based glow nanoparticles probe, ICG-Glow NPs) for the cancer cell/tissue-specific targeting. The self-assembled ICG-Glow NPs were confirmed by spherical nanoparticles formation (DLS and TEM) and spectral analyses. The NIRF imaging characteristic of ICG-Glow NPs was established by superior fluorescence counts on filter paper and chicken tissue. The ICG-Glow NPs exhibited excellent hemo and cellular compatibility with human red blood cells, kidney normal, pancreatic normal, and other cancer cell lines. An enhanced cancer-specific NIRF binding and imaging capability of ICG-Glow NPs was confirmed using different human cancer cell lines and human tumor tissues. Additionally, tumor-specific binding/accumulation of ICG-Glow NPs was confirmed in MDA-MB-231 xenograft mouse model. Collectively, these findings suggest that ICG-Glow NPs have great potential as a novel and safe NIRF imaging probe for cancer cell/tumor imaging. This can lead to a quicker cancer diagnosis facilitating precise disease detection and management.
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Neoplasias , Nanopartículas , Verde de Indocianina , Neoplasias/diagnóstico por imagen , Humanos , Línea Celular , Femenino , Animales , RatonesRESUMEN
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.
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Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Calcio/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo/fisiologíaRESUMEN
The composition of resident microbes in the human body is linked to various diseases and their treatment outcomes. Although studies have identified pancreatic ductal adenocarcinoma (PDAC)-associated bacterial communities in the oral and gut samples, herein, we hypothesize that the prevalence of microbiota in pancreatic tumor tissues is different as compared with their matched adjacent, histologically normal appearing tissues, and these microbial molecular signatures can be highly useful for PDAC diagnosis/prognosis. In this study, we performed comparative profiling of bacterial populations in pancreatic tumors and their respective adjacent normal tissues using 16S rRNA-based metagenomics analysis. This study revealed a higher abundance of Proteobacteria and Actinomycetota in tumor tissues compared with adjacent normal tissues. Interestingly, the linear discriminant analysis (LDA) scores unambiguously revealed an enrichment of Delftia in tumor tissues, whereas Sphingomonas, Streptococcus, and Citrobacter exhibited a depletion in tumor tissues. Furthermore, we analyzed the microbial composition between different groups of patients with different tumor differentiation stages. The bacterial genera, Delftia and Staphylococcus, were very high at the G1 stages (well differentiated) compared with G2 (well to moderate/moderately differentiated) and G3/G4 (poorly differentiated) stages. However, the abundance of Actinobacter and Cloacibacterium was found to be very high in G2 and G3, respectively. Additionally, we evaluated the correlation of programmed death-ligand (PDL1) expression with the abundance of bacterial genera in tumor lesions. Our results indicated that three genera such as Streptomyces, Cutibacterium, and Delftia have a positive correlation with PD-L1 expression. Collectively, these findings demonstrate that PDAC lesions harbor relatively different microbiota compared with their normal tumor adjacent tissues, and this information may be helpful for the diagnosis and prognosis of PADC patients.
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Nonsmall-cell lung cancer (NSCLC) is the most common type of lung cancer, with a dismal prognosis. NSCLC is a highly vascularized tumor, and chemotherapy is often hampered by the development of angiogenesis. Therefore, suppression of angiogenesis is considered a potential treatment approach. Tannic acid (TA), a natural polyphenol, has been demonstrated to have anticancer properties in a variety of cancers; however, its angiogenic properties have yet to be studied. Hence, in the current study, we investigated the antiproliferative and antiangiogenic effects of TA on NSCLC cells. The (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay revealed that TA induced a dose- and time-dependent decrease in the proliferation of A549 and H1299 cells. However, TA had no significant toxicity effects on human bronchial epithelial cells. Clonogenicity assay revealed that TA suppressed colony formation ability in NSCLC cells in a dose-dependent manner. The anti-invasiveness and antimigratory potential of TA were confirmed by Matrigel and Boyden chamber studies, respectively. Importantly, TA also decreased the ability of human umbilical vein endothelial cells (HUVEC) to form tube-like networks, demonstrating its antiangiogenic properties. Extracellular vascular endothelial growth factor (VEGF) release was reduced in TA-treated cells compared to that in control cells, as measured by the enzyme-linked immunosorbent assay (ELISA). Overall, these results demonstrate that TA can induce antiproliferative and antiangiogenic effects against NSCLC.
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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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Chemotherapy is one of the prime treatment options for cancer. However, the key issues with traditional chemotherapy are recurrence of cancer, development of resistance to chemotherapeutic agents, affordability, late-stage detection, serious health consequences, and inaccessibility. Hence, there is an urgent need to find innovative and cost-effective therapies that can target multiple gene products with minimal adverse reactions. Natural phytochemicals originating from plants constitute a significant proportion of the possible therapeutic agents. In this article, we reviewed the advances and the potential of Withania somnifera (WS) as an anticancer and immunomodulatory molecule. Several preclinical studies have shown the potential of WS to prevent or slow the progression of cancer originating from various organs such as the liver, cervix, breast, brain, colon, skin, lung, and prostate. WS extracts act via various pathways and provide optimum effectiveness against drug resistance in cancer. However, stability, bioavailability, and target specificity are major obstacles in combination therapy and have limited their application. The novel nanotechnology approaches enable solubility, stability, absorption, protection from premature degradation in the body, and increased circulation time and invariably results in a high differential uptake efficiency in the phytochemical's target cells. The present review primarily emphasizes the insights of WS source, chemistry, and the molecular pathways involved in tumor regression, as well as developments achieved in the delivery of WS for cancer therapy using nanotechnology. This review substantiates WS as a potential immunomodulatory, anticancer, and chemopreventive agent and highlights its potential use in cancer treatment.
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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
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
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease affecting both upper and lower motor neurons. In the United States alone, there are 16,000-20,000 established cases of ALS. The early disease diagnosis is challenging due to many overlapping pathophysiologies with other neurological diseases. The etiology of ALS is unknown; however, it is divided into two categories: familial ALS (fALS) which occurs due to gene mutations & contributes to 5-10% of ALS, and sporadic ALS (sALS) which is due to environmental factors & contributes to 90-95% of ALS. There is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. In this review, we provide a panoramic view of ALS, which includes epidemiology, risk factors, pathophysiologies, biomarkers, diagnosis, therapeutics (natural, synthetic, gene-based, pharmacological, stem cell, extracellular vesicles, and physical therapy), controversies (in the clinical trials of ALS), the scope of nanomedicine in ALS, and future perspectives.