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Stress is the major unseen bug for the health of humans with the increasing workaholic era. Long periods of avoidance are the main precursor for chronic disorders that are quite tough to treat. As precaution is better than cure, stress detection and monitoring are vital. Although there are ways to measure stress clinically, there is still a constant need and demand for methods that measure stress personally and in an ex vitro manner for the convenience of the user. The concept of continuous stress monitoring has been introduced to tackle the issue of unseen stress accumulating in the body simultaneously with being user-friendly and reliable. Stress biosensors nowadays provide real-time, noninvasive, and continuous monitoring of stress. These biosensors are innovative anthropogenic creations that are a combination of biomarkers and indicators like heart rate variation, electrodermal activity, skin temperature, galvanic skin response, and electroencephalograph of stress in the body along with machine learning algorithms and techniques. The collaboration of biological markers, artificial intelligence techniques, and data science tools makes stress biosensors a hot topic for research. These attributes have made continuous stress detection a possibility with ease. The advancement in stress biosensing technologies has made a great impact on the lives of human beings so far. This article focuses on the comprehensive study of stress-indicating biomarkers and the techniques along with principles of the biosensors used for continuous stress detection. The precise overview of wearable stress monitoring systems is also sectioned to pave a pathway for possible future research studies.
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Técnicas Biossensoriais , Dispositivos Eletrônicos Vestíveis , Humanos , Inteligência Artificial , Técnicas Biossensoriais/métodos , Monitorização Fisiológica/métodos , BiomarcadoresRESUMO
One important phytochemical is naringenin, which belongs to the flavanone class of polyphenols. It is found in citrus fruits, such as grapefruits, but it can also be found in tomatoes, cherries, and other food-grade medicinal plants. Naringenin has a significant chemotherapeutic promise, as several investigations have conclusively shown. Therefore, the goal of this review is to synthesize the literature that has been done on naringenin as a possible anti-cancer agent and clarify the mechanisms of action that have been described in treatment plans for different kinds of cancer. In a variety of cancer cells, naringenin works by affecting several pathways associated with cell cycle arrest, anti-metastasis, apoptosis, anti-angiogenesis, and DNA repair. It has been shown to alter several molecular targets linked to the development of cancer, such as drug transporters, transcription factors, reactive nitrogen species, reactive oxygen species, cellular kinases, and inflammatory cytokines and regulators of the cell cycle. In summary, this research provides significant insights into the potential of naringenin as a strong and prospective candidate for use in medicines, nutraceuticals, functional foods, and dietary supplements to improve the management of carcinoma.
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Androgen (AR) signaling is the main signaling for the development of the prostate and its normal functioning. AR is highly specific for testosterone and dihydrotestosterone, significantly contributing to prostate development, physiology, and cancer. All these receptors have emerged as crucial therapeutic targets for PCa. In the year 1966, the Noble prize was awarded to Huggins and Hodge for their groundbreaking discovery of AR. As it is a pioneer transcription factor, it belongs to the steroid hormone receptor family and consists of domains, including DNA binding domain (DBD), hormone response elements (HRE), C-terminal ligand binding domain (LBD), and N-terminal regulatory domains. Structural variations in AR, such as AR gene amplification, LBD mutations, alternative splicing of exons, hypermethylation of AR, and co- regulators, are major contributors to PCa. It's signaling is crucial for the development and functioning of the prostate gland, with the AR being the key player. The specificity of AR for testosterone and dihydrotestosterone is important in prostate physiology. However, when it is dysregulated, AR contributes significantly to PCa. However, the structural variations in AR, such as gene amplification, mutations, alternative splicing, and epigenetic modifications, drive the PCa progression. Therefore, understanding AR function and dysregulation is essential for developing effective therapeutic strategies. Thus, the aim of this review was to examine how AR was initially pivotal for prostate development and how it turned out to show both positive and detrimental implications for the prostate.
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One of the biggest obstacles to the treatment of diseases, particularly serious conditions like cancer, is therapeutic resistance. The process of drug resistance is influenced by a number of important variables, including MDR genes, drug efflux, low-quality medications, inadequate dosage, etc. Drug resistance must be addressed, and new combinations based on the pharmacokinetics/pharmacodynamics (PK-PD) characteristics of the partner pharmaceuticals must be developed in order to extend the half-lives of already available medications. The primary mechanism of drug elimination is hepatic biotransformation of medicines by cytochrome P450 (CYP) enzymes; of these CYPs, CYP3A4 makes up 30-40% of all known cytochromes that metabolize medications. Induction or inhibition of CYP3A4-mediated metabolism affects the pharmacokinetics of most anticancer drugs, but these details are not fully understood and highlighted because of the complexity of tumor microenvironments and various influencing patient related factors. The involvement of CYPs, particularly CYP3A4 and other drug-metabolizing enzymes, in cancer medication resistance will be covered in the current review.
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Round cell tumors are a group of malignant tumors which shows overlapping microscopic features of small round monotonous cells with hyper-chromatic nucleus. It mostly occurs in children, adolescent, and young adults. The ancillary technique to confirm the differential diagnosis of round cells sarcoma is immuno-histo chemistry (IHC). Therefore, it is of interest to document the diversity of small round cell sarcoma in soft tissues around bones among Indian patients using IHC. A total of 334 cases among Indians were studied. Among them 160 cases were Non-Hodgkin's Lymphoma, 82 cases are poorly differentiated carcinoma and 92 cases of round cell sarcoma. Out of 92 cases, there were (40%) 27 cases of Wilms tumour, with the highest incidence. The highest incidence was observed in 0-14 years of age group with highest incidence in males. The distribution and diverse histology of different small round cell sarcoma offers challenge in the diagnosis by histopathology. Most frequent round cell tumour is Wilms tumour, followed by Rhabdomyosarcoma. Data shows the role of IHC in classifying soft tissue sarcoma but some time result of IHC remains inconclusive, where cytogenetic is important.
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Background Tumor budding (TB) has been identified in many solid cancers and thought to be involved in invasion and is the initial step in the metastatic process. Limited information is available documenting the role of tumor budding in breast carcinoma. With this aim, the present study evaluates the association of tumor budding, tumor microenvironment, and its correlation with clinicopathologic parameters. Materials and Methods A total of 102 cases were archived and evaluated for peripheral and intra tumoral budding along with tumor microenvironment on hematoxylin and eosin (H&E) slides. Statistical Analysis Correlation between tumor budding, tumor microenvironment, and other classical clinicopathological parameters was studied by Chi-square test. A p -value less than 0.05 was considered significant. Results Females constituted 99 cases out of 102 and 3 were males. We found 55.9% and 44.1% of patients in the age group less than or equal to 50 and greater than 50, respectively. Also, 65.6% of cases presented with small tumor size less than or equal to 5 cm, 80.39% with lymph node metastasis, and 76.4% with lympho-vascular emboli. High peripheral tumoral budding (PTB) was seen in 45.10%, low peripheral tumoral budding in 54.9%, high ITB in 53.9%, and low ITB in 46.1%. Necrosis was found only in 39.21%. Significant statistical association of PTB was found with lymph node metastasis, lymphovascular emboli, and tumor necrosis, whereas ITB with tumor grade, lymph node metastasis, lympho-vascular emboli, and necrosis. Both PTB and ITB showed no statistically significant correlation with age and size of the tumor. Conclusion Tumor budding is an independent adverse prognostic factor in invasive breast carcinoma. However, further work is needed to establish a standard method for the quantification of this parameter, which will help in effective stratification of patients in terms of disease-free survival and likely outcome.
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The directed differentiation of pluripotent stem cells to a desired lineage often involves complex and lengthy protocols. In order to study the requirements for differentiation in a systematic way, we present here methodology for an iterative approach using combinations of small molecules and biological factors. The factors are used in a cyclical process in which the best combination of factors and concentrations is selected in one round of testing, followed by a modification of the combination and subsequent rounds. While this may produce the desired differentiation in the cell population under study, it is also possible that other strategies may be needed to optimize the differentiation process. These strategies are described in this chapter.
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Diferenciação Celular , Células-Tronco Pluripotentes/citologia , Animais , Biomarcadores , Callithrix , Diferenciação Celular/genética , Linhagem Celular , Células-Tronco Pluripotentes/metabolismoRESUMO
Intranasal administration is a promising route of delivery of stem cells to the central nervous system (CNS). Reports on this mode of stem cell delivery have not yet focused on the route across the cribriform plate by which cells move from the nasal cavity into the CNS. In the current experiments, human mesenchymal stem cells (MSCs) were isolated from Wharton's jelly of umbilical cords and were labeled with extremely bright quantum dots (QDs) in order to track the cells efficiently. At 2 h after intranasal delivery in immunodeficient mice, the labeled cells were found under the olfactory epithelium, crossing the cribriform plate adjacent to the fila olfactoria, and associated with the meninges of the olfactory bulb. At all times, the cells were separate from actual nerve tracts; this location is consistent with them being in the subarachnoid space (SAS) and its extensions through the cribriform plate into the nasal mucosa. In their location under the olfactory epithelium, they appear to be within an expansion of a potential space adjacent to the turbinate bone periosteum. Therefore, intranasally administered stem cells appear to cross the olfactory epithelium, enter a space adjacent to the periosteum of the turbinate bones, and then enter the SAS via its extensions adjacent to the fila olfactoria as they cross the cribriform plate. These observations should enhance understanding of the mode by which stem cells can reach the CNS from the nasal cavity and may guide future experiments on making intranasal delivery of stem cells efficient and reproducible.
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Sistema Nervoso Central/citologia , Células-Tronco Mesenquimais/citologia , Células-Tronco/citologia , Células Cultivadas , Humanos , Imuno-Histoquímica , Microscopia de Fluorescência , Nanopartículas/química , Nanotecnologia/métodos , Pontos Quânticos , Geleia de Wharton/citologiaRESUMO
Induced pluripotent stem cells (iPS cells) generated by cellular reprogramming from nonhuman primates (NHPs) are of great significance for regenerative medicine and for comparative biology. Autologously derived stem cells would theoretically avoid any risk of rejection due to host-donor mismatch and may bypass the need for immune suppression post-transplant. In order for these possibilities to be realized, reprogramming methodologies that were initially developed mainly for human cells must be translated to NHPs. NHP studies have typically used pluripotent cells generated from young animals and thus risk overlooking complications that may arise from generating iPS cells from donors of other ages. When reprogramming is extended to a wide range of NHP species, available donors may be middle- or old-aged. Here we have pursued these questions by generating iPS cells from donors across the life span of the common marmoset (Callithrix jacchus) and then subjecting them to a directed neural differentiation protocol. The differentiation potential of different clonal cell lines was assessed using the quantitative polymerase chain reaction. The results show that cells derived from older donors often showed less neural marker induction. These deficits were rescued by a 24â¯h pretreatment of the cells with 0.5â¯% dimethyl sulfoxide. Another NHP that plays a key role in biological research is the chimpanzee (Pan troglodytes). iPS cells generated from the chimpanzee can be of great interest in comparative in vitro studies. We investigated if similar deficits in differentiation potential might arise in chimpanzee iPS cells reprogrammed using various technologies. The results show that, while some deficits were observed in iPS cell clones generated using three different technologies, there was no clear association with the vector used. These deficits in differentiation were also prevented by a 24â¯h pretreatment with 0.5â¯% dimethyl sulfoxide.
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Induced pluripotent stem cells from nonhuman primates (NHPs) have unique roles in cell biology and regenerative medicine. Because of the relatedness of NHPs to humans, NHP iPS cells can serve as a source of differentiated derivatives that can be used to address important questions in the comparative biology of primates. Additionally, when used as a source of cells for regenerative medicine, NHP iPS cells serve an invaluable role in translational experiments in cell therapy. Reprogramming of NHP somatic cells requires the same conditions as previously established for human cells. However, throughout the process, a variety of modifications to the human cell protocols must be made to accommodate significant species differences.
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Células-Tronco Pluripotentes Induzidas/citologia , Primatas , Transgenes , Animais , Callithrix , Técnicas de Cultura de Células/métodos , Células Cultivadas , Reprogramação Celular , Técnicas de Reprogramação Celular/métodos , Fibroblastos/citologia , Genes myc , Vetores Genéticos/genética , Humanos , Células-Tronco Pluripotentes Induzidas/transplante , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/fisiologia , Camundongos , Camundongos Knockout , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/fisiologia , Proteínas Proto-Oncogênicas c-myb/fisiologia , Retroviridae/genética , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/fisiologia , Especificidade da Espécie , Teratoma/patologiaRESUMO
The marmoset is an important nonhuman primate model for regenerative medicine. For experimental autologous cell therapy based on induced pluripotent (iPS) cells in the marmoset, cells must be able to undergo robust and reliable directed differentiation that will not require customization for each specific iPS cell clone. When marmoset iPS cells were aggregated in a hanging drop format for 3 days, followed by exposure to dual SMAD inhibitors and retinoic acid in monolayer culture for 3 days, we found substantial variability in the response of different iPS cell clones. However, when clones were pretreated with 0.05-2% dimethyl sulfoxide (DMSO) for 24 hours, all clones showed a very similar maximal response to the directed differentiation scheme. Peak responses were observed at 0.5% DMSO in two clones and at 1% DMSO in a third clone. When patterns of gene expression were examined by microarray analysis, hierarchical clustering showed very similar responses in all 3 clones when they were pretreated with optimal DMSO concentrations. The change in phenotype following exposure to DMSO and the 6 day hanging drop/monolayer treatment was confirmed by immunocytochemistry. Analysis of DNA content in DMSO-exposed cells indicated that it is unlikely that DMSO acts by causing cells to exit from the cell cycle. This approach should be generally valuable in the directed neural differentiation of pluripotent cells for experimental cell therapy.
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Diferenciação Celular/efeitos dos fármacos , Dimetil Sulfóxido/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Neurônios/citologia , Animais , Callithrix , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Diferenciação Celular/genética , Linhagem Celular , Imuno-Histoquímica , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos TestesRESUMO
Induced pluripotent stem cells (iPS cells) are important for the future development of regenerative medicine involving autologous cell therapy. Before autologous cell therapy can be applied to human patients, suitable animal models must be developed, and in this context non-human primate models are critical. We previously characterized several lines of marmoset iPS cells derived from newborn skin fibroblasts. In the present studies, we explored methods for the directed differentiation of marmoset iPS cells in the neuroectodermal lineage. In this process we used an iterative process in which combinations of small molecules and protein factors were tested for their effects on mRNA levels of genes that are markers for the neuroectodermal lineage. This iterative process identified combinations of chemicals/factors that substantially improved the degree of marker gene expression over the initially tested combinations. This approach should be generally valuable in the directed differentiation of pluripotent cells for experimental cell therapy.
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Técnicas de Cultura de Células , Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/fisiologia , Neurônios/citologia , Animais , Callithrix , Linhagem da Célula , Expressão Gênica/efeitos dos fármacos , Marcadores Genéticos , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , RNA Mensageiro/metabolismoRESUMO
The development of the technology for derivation of induced pluripotent stem (iPS) cells from human patients and animal models has opened up new pathways to the better understanding of many human diseases, and has created new opportunities for therapeutic approaches. Here, we consider one important neurological disease, Parkinson's, the development of relevant neural cell lines for studying this disease, and the animal models that are available for testing the survival and function of the cells, following transplantation into the central nervous system. Rapid progress has been made recently in the application of protocols for neuroectoderm differentiation and neural patterning of pluripotent stem cells. These developments have resulted in the ability to produce large numbers of dopaminergic neurons with midbrain characteristics for further study. These cells have been shown to be functional in both rodent and nonhuman primate (NHP) models of Parkinson's disease. Patient-specific iPS cells and derived dopaminergic neurons have been developed, in particular from patients with genetic causes of Parkinson's disease. For complete modeling of the disease, it is proposed that the introduction of genetic changes into NHP iPS cells, followed by studying the phenotype of the genetic change in cells transplanted into the NHP as host animal, will yield new insights into disease processes not possible with rodent models alone.
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Among the various species from which induced pluripotent stem cells have been derived, nonhuman primates (NHPs) have a unique role as preclinical models. Their relatedness to humans and similar physiology, including central nervous system, make them ideal for translational studies. We review here the progress made in deriving and characterizing iPS cell lines from different NHP species. We focus on iPS cell lines from the marmoset, a small NHP in which several human disease states can be modeled. The marmoset can serve as a model for the implementation of patient-specific autologous cell therapy in regenerative medicine.
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Cell- and tissue-based biosensors comprise genetically engineered proteins that are incorporated into cells ex vivo or into cells of tissues in vivo. They enable the investigator to sense levels of hormones, drugs, or toxins, continuously and noninvasively, using biophotonics or other physical principles, and could potentially be used over the entire lifespan of an experimental animal. The present work reviews the state of the art of cell- and tissue-based biosensors and discusses how they could be of value in aging research. Examples of recently developed biosensors are given, including those that detect levels of a cytokine (TNFα) and drugs (activators of the mTOR pathway). Finally, we discuss the hurdles that would have to be overcome for biosensor technology to be used in humans in monitoring health status and disease treatment in late life.
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Envelhecimento/fisiologia , Pesquisa Biomédica/métodos , Técnicas Biossensoriais/métodos , Modelos Animais de Doenças , Modelos Animais , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Pesquisa Biomédica/instrumentação , Pesquisa Biomédica/tendências , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/tendências , Geriatria/métodos , Geriatria/tendências , HumanosRESUMO
Induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine. For the application of iPSCs to forms of autologous cell therapy, suitable animal models are required. Among species that could potentially be used for this purpose, nonhuman primates are particularly important, and among these the marmoset offers significant advantages. In order to demonstrate the feasibility of the application of iPSC technology to this species, here we derived lines of marmoset iPSCs. Using retroviral transduction with human Oct4, Sox2, Klf4 and c-Myc, we derived clones that fulfil critical criteria for successful reprogramming: they exhibit typical iPSC morphology; they are alkaline phosphatase positive; they express high levels of NANOG, OCT4 and SOX2 mRNAs, while the corresponding vector genes are silenced; they are immunoreactive for Oct4, TRA-1-81 and SSEA-4; and when implanted into immunodeficient mice they produce teratomas that have derivatives of all three germ layers (endoderm, alpha-fetoprotein; ectoderm, betaIII-tubulin; mesoderm, smooth muscle actin). Starting with a population of 4 x 10(5) newborn marmoset skin fibroblasts, we obtained approximately 100 colonies with iPSC-like morphology. Of these, 30 were expanded sufficiently to be cryopreserved, and, of those, 8 were characterized in more detail. These experiments provide proof of principle that iPSC technology can be adapted for use in the marmoset, as a future model of autologous cell therapy.