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1.
Proc Natl Acad Sci U S A ; 120(8): e2205247120, 2023 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-36780531

RESUMEN

Brain metastases (BM) are the most common brain neoplasm in adults. Current BM therapies still offer limited efficacy and reduced survival outcomes, emphasizing the need for a better understanding of the disease. Herein, we analyzed the transcriptional profile of brain metastasis initiating cells (BMICs) at two distinct stages of the brain metastatic cascade-the "premetastatic" or early stage when they first colonize the brain and the established macrometastatic stage. RNA sequencing was used to obtain the transcriptional profiles of premetastatic and macrometastatic (non-premetastatic) lung, breast, and melanoma BMICs. We identified that lung, breast, and melanoma premetastatic BMICs share a common transcriptomic signature that is distinct from their non-premetastatic counterparts. Importantly, we show that premetastatic BMICs exhibit increased expression of HLA-G, which we further demonstrate functions in an HLA-G/SPAG9/STAT3 axis to promote the establishment of brain metastatic lesions. Our findings suggest that unraveling the molecular landscape of premetastatic BMICs allows for the identification of clinically relevant targets that can possibly inform the development of preventive and/or more efficacious BM therapies.


Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Mama , Antígenos HLA-G , Neoplasias Pulmonares , Melanoma , Adulto , Humanos , Proteínas Adaptadoras Transductoras de Señales , Encéfalo/patología , Neoplasias Encefálicas/secundario , Antígenos HLA-G/genética , Pulmón/patología , Neoplasias Pulmonares/patología , Melanoma/patología , Factor de Transcripción STAT3/genética , Neoplasias de la Mama/patología
2.
Mol Biol Rep ; 50(11): 9453-9468, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37676432

RESUMEN

Osteoporosis is a metabolic bone disorder that over time results in bone loss and raises the risk of fracture. The condition is frequently silent and only becomes apparent when fractures develop. Osteoporosis is treated with pharmacotherapy as well as non-pharmacological therapies such as mineral supplements, lifestyle changes, and exercise routines. Herbal medicine is frequently used in clinical procedures because of its low risk of adverse effects and cost-effective therapeutic results. In the current review, we have used a thorough strategy to identify some known medicinal plants with anti-osteoporosis capabilities, their origin, active ingredients, and pharmacological information. Furthermore, several signaling pathways, such as the apoptotic pathway, transcription factors, the Wnt/-catenin signaling pathway, and others, are regulated by bioactive components and help to improve bone homeostasis. This review will provide a better understanding of the anti-osteoporotic effects of bioactive components and the concomitant modulations of signaling pathways.


Asunto(s)
Fracturas Óseas , Osteoporosis , Plantas Medicinales , Humanos , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Huesos/metabolismo , Medicina de Hierbas , Osteogénesis
3.
J Plant Res ; 136(5): 587-612, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37452973

RESUMEN

Asteraceae (synonym as Compositae) is one of the largest angiosperm families among flowering plants comprising one-tenth of all agri-horticultural species grown across various habitats except in Antarctica. These are commercially utilized as cut and loose flowers as well as pot and bedding plants in landscape gardens due to their unique floral traits. Consequently, ineffective seed setting and presence of an intraspecific reproductive barrier known as self-incompatibility (SI) severely reduces the effectiveness of hybridization and self-fertilization by traditional crossing. There have been very few detailed studies of pollen-stigma interactions in this family. Moreover, about 63% of Aster species can barely self-fertilize due to self-incompatibility (SI). The chrysanthemum (Chrysanthemum × morifolium) is one of the most economically important ornamental plants in the Asteraceae family which hugely shows incompatibility. Reasons for the low fertility and reproductive capacity of species are still indefinite or not clear. Hence, the temporal pattern of inheritance of self-incompatibility and its effect on reproductive biology needs to be investigated further to improve the breeding efficiency. This review highlights the self-incompatible (SI) system operating in important Astraceous (ornamental) crops which are adversely affected by this mechanism along with different physiological and molecular techniques involved in breaking down self-incompatibility.

4.
Lett Appl Microbiol ; 76(1)2023 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-36688751

RESUMEN

Clustered regularly interspaced short palindromic repeats (CRISPRs) are known to provide adaptive immunity to bacteria against invading bacteriophages. In recent years, CRISPR-based technologies have been used for creating improved plant varieties; however, the indigenous CRISPR-Cas elements of plant growth-promoting bacteria are usually neglected. These indigenous genetic cassettes have evolved over millions of years and have shaped the bacterial genome. Therefore, these genetic loci can be used to study the adaptive capability of the bacteria in the environment. This study aims to bioinformatically analyze the genomes of a common free-living nitrogen-fixing Azotobacter spp. to assess their CRISPR-Cas diversity. Strains of Azotobacter vinelandii and Azotobacter chroococcum were found to harbor a large number of spacers. The phylogeny of different Cas and Cse1 proteins revealed a close evolutionary relationship among A. chroococcum B3, A. chroococcum NCIMB 8003 locus II, and A. vinelandii DJ locus I. The secondary structure of the hairpin loop of the repeat was also analyzed, and a correlation was derived between the structural stability of the hairpin loop and the number of spacers acquired by the CRISPR loci. These findings revealed the diversity and evolution of the CRISPR sequences and Cas proteins in Azotobacter species. Although the adaptive immune system of bacteria against bacteriophage, CRISPR-Cas, has been identified in many bacteria, studies of plant growth-promoting bacteria have been neglected. These indigenous CRISPRs have shaped the genome over millions of years and their study can lead to the understanding of the genome composition of these organisms. Our results strengthen the idea of using A. chroococcum and A. vinelandii as biofertilizer strains as they possess more spacers with highly stable repeat sequences, thereby imparting them higher chance of survival against mobile genetic elements like phages and plasmids.


Asunto(s)
Azotobacter , Bacteriófagos , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Sistemas CRISPR-Cas , Genómica , Bacterias/genética , Azotobacter/genética , Bacteriófagos/genética
5.
Genomics ; 114(2): 110269, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35065190

RESUMEN

The development and utilization of molecular-markers play an important role in genomics-assisted breeding during pyramiding of valuable genes. The aim of present study was to develop and validate a novel core-set of KASP (Kompetitive Allele-Specific PCR) markers associated with traits improving rice grain yield and adaptability under direct-seeded cultivation conditions. The 110 phenotypically validated KASP assays out of 171 designed KASP, include assays for biotic-resistance genes, anaerobic germination, root-traits, grain yield, lodging resistance and early-uniform emergence. The KASP assays were validated for their robustness and reliability at five different levels using diverse germplasm, segregating and advanced population, comparison with SSR markers and on F1s. The present research work will provide (i) breeding material in form of anticipated pre-direct-seeded adapted rice varieties (ii) single improved breeding line with many useful genes and (iii) KASP assay information for the useful QTL/genes providing grain yield and adaptability to rice under direct-seeded cultivation conditions.


Asunto(s)
Oryza , Grano Comestible/genética , Oryza/genética , Fenotipo , Fitomejoramiento , Reproducibilidad de los Resultados
6.
Plant Mol Biol ; 105(1-2): 161-175, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32997301

RESUMEN

KEY MESSAGE: Genome wide association studies allowed prediction of 17 candidate genes for association with nitrogen use efficiency. Novel information obtained may provide better understanding of genomic controls underlying germplasm variations for this trait in Indian mustard. Nitrogen use efficiency (NUE) of Indian mustard (Brassica juncea (L.) Czern & Coss.) is low and most breeding efforts to combine NUE with crop performance have not succeeded. Underlying genetics also remain unexplored. We tested 92 SNP-genotyped inbred lines for yield component traits, N uptake efficiency (NUPEFF), nitrogen utilization efficiency (NUTEFF), nitrogen harvest index (NHI) and NUE for two years at two nitrogen doses (No without added N and N100 added @100 kg/ha). Genotypes IC-2489-88, M-633, MCP-632, HUJM 1080, GR-325 and DJ-65 recorded high NUE at low N. These also showed improved crop performance under high N. One determinate mustard genotype DJ-113 DT-3 revealed maximum NUTEFF. Genome wide association studies (GWAS) facilitated recognition of 17 quantitative trait loci (QTLs). Environment specificity was high. B-genome chromosomes (B02, B03, B05, B07 and B08) harbored many useful loci. We also used regional association mapping (RAM) to supplement results from GWAS. Annotation of the genomic regions around peak SNPs helped to predict several gene candidates for root architecture, N uptake, assimilation and remobilization. CAT9 (At1g05940) was consistently envisaged for both NUE and NUPEFF. Major N transporter genes, NRT1.8 and NRT3.1 were predicted for explaining variation for NUTEFF and NUPEFF, respectively. Most significant amino acid transporter gene, AAP1 appeared associated with NUE under limited N conditions. All these candidates were predicted in the regions of high linkage disequilibrium. Sequence information of the predicted candidate genes will permit development of molecular markers to aid breeding for high NUE.


Asunto(s)
Planta de la Mostaza/genética , Planta de la Mostaza/metabolismo , Nitrógeno/metabolismo , Genes de Plantas , Estudio de Asociación del Genoma Completo , Genotipo , Desequilibrio de Ligamiento , Fenotipo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo
7.
Oncologist ; 26(3): 231-241, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33103803

RESUMEN

Brain metastases account for considerable morbidity and mortality in patients with cancer. Despite increasing prevalence, limited therapeutic options exist. Recent advances in our understanding of the molecular and cellular underpinnings of the tumor immune microenvironment and the immune evasive mechanisms employed by tumor cells have shed light on how immunotherapies may provide therapeutic benefit to patients. The development and evolution of immunotherapy continue to show promise for the treatment of brain metastases. Positive outcomes have been observed in several studies evaluating the efficacy and safety of these treatments. However, many challenges persist in the application of immunotherapies to brain metastases. This review discusses the potential benefits and challenges in the development and use of checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and oncolytic viruses for the treatment of brain metastases. Future studies are necessary to further evaluate and assess the potential use of each of these therapies in this setting. As we gain more knowledge regarding the role immunotherapies may play in the treatment of brain metastases, it is important to consider how these treatments may guide clinical decision making for clinicians and the impact they may have on patients. IMPLICATIONS FOR PRACTICE: Immunotherapies have produced clinically significant outcomes in early clinical trials evaluating patients with brain metastases or demonstrated promising results in preclinical models. Checkpoint inhibitors have been the most common immunotherapy studied to date in the setting of brain metastases, but novel approaches that can harness the immune system to contain and eliminate cancer cells are currently under investigation and may soon become more common in the clinical setting. An understanding of these evolving therapies may be useful in determining how the future management and treatment of brain metastases among patients with cancer will continue to advance.


Asunto(s)
Neoplasias Encefálicas , Inmunoterapia , Neoplasias Encefálicas/terapia , Humanos , Microambiente Tumoral
8.
J Neurooncol ; 143(3): 417-428, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31115870

RESUMEN

PURPOSE: Glioblastoma (GBM) is the most aggressive adult brain cancer, with a 15 month median survivorship attributed to the existence of treatment-refractory brain tumor initiating cells (BTICs). In order to better understand the mechanisms regulating the tumorigenic properties of this population, we studied the role of the polycomb group member BMI1 in our patient-derived GBM BTICs and its relationship with CD133, a well-established marker of BTICs. METHODS: Using gain and loss-of-function studies for Bmi1 in neural stem cells (NSCs) and patient-derived GBM BTICs respectively, we assessed in vitro self-renewal and in vivo tumor formation in these two cell populations. We further explored the BMI1 transcriptional regulatory network through RNA sequencing of different GBM BTIC populations that were knocked down for Bmi1. RESULTS: There is a differential role of BMI1 in CD133-positive cells, notably involving cell metabolism. In addition, we identified pivotal targets downstream of BMI1 in CD133+ cells such as integrin alpha 2 (ITGA2), that may contribute to regulating GBM stem cell properties. CONCLUSIONS: Our work sheds light on the association of three genes with CD133-BMI1 circuitry, their importance as downstream effectors of the BMI1 signalling pathway, and their potential as future targets for tackling GBM treatment-resistant cell populations.


Asunto(s)
Antígeno AC133/metabolismo , Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Glioblastoma/patología , Células Madre Neoplásicas/patología , Complejo Represivo Polycomb 1/metabolismo , Antígeno AC133/genética , Animales , Apoptosis , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferación Celular , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células Madre Neoplásicas/metabolismo , Complejo Represivo Polycomb 1/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Acta Neuropathol ; 134(6): 923-940, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28766011

RESUMEN

Brain metastases (BM) are the most common brain tumor in adults and are a leading cause of cancer mortality. Metastatic lesions contain subclones derived from their primary lesion, yet their functional characterization is limited by a paucity of preclinical models accurately recapitulating the metastatic cascade, emphasizing the need for a novel approach to BM and their treatment. We identified a unique subset of stem-like cells from primary human patient brain metastases, termed brain metastasis-initiating cells (BMICs). We now establish a BMIC patient-derived xenotransplantation (PDXT) model as an investigative tool to comprehensively interrogate human BM. Using both in vitro and in vivo RNA interference screens of these BMIC models, we identified SPOCK1 and TWIST2 as essential BMIC regulators. SPOCK1 in particular is a novel regulator of BMIC self-renewal, modulating tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens showed that SPOCK1 was overexpressed only in patients who ultimately developed BM. Protein-protein interaction network mapping between SPOCK1 and TWIST2 identified novel pathway interactors with significant prognostic value in lung cancer patients. Of these genes, INHBA, a TGF-ß ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1. In conclusion, we have developed a useful preclinical model of BM, which has served to identify novel putative BMIC regulators, presenting potential therapeutic targets that block the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/fisiopatología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Neoplasias Encefálicas/fisiopatología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Línea Celular Tumoral , Femenino , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Trasplante de Neoplasias , Estudios Prospectivos , Proteoglicanos/genética , Proteoglicanos/metabolismo , Interferencia de ARN , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismo
10.
Int J Mol Sci ; 15(5): 9117-33, 2014 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-24857921

RESUMEN

Brain metastases (BMs) are the most common brain tumor in adults, developing in about 10% of adult cancer patients. It is not the incidence of BM that is alarming, but the poor patient prognosis. Even with aggressive treatments, median patient survival is only months. Despite the high rate of BM-associated mortality, very little research is conducted in this area. Lack of research and staggeringly low patient survival is indicative that a novel approach to BMs and their treatment is needed. The ability of a small subset of primary tumor cells to produce macrometastases is reminiscent of brain tumor-initiating cells (BTICs) or cancer stem cells (CSCs) hypothesized to form primary brain tumors. BTICs are considered stem cell-like due to their self-renewal and differentiation properties. Similar to the subset of cells forming metastases, BTICs are most often a rare subpopulation. Based on the functional definition of a TIC, cells capable of forming a BM could be considered to be brain metastasis-initiating cells (BMICs). These putative BMICs would not only have the ability to initiate tumor growth in a secondary niche, but also the machinery to escape the primary tumor, migrate through the circulation, and invade the neural niche.


Asunto(s)
Neoplasias Encefálicas/patología , Células Madre Neoplásicas/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Invasividad Neoplásica , Células Neoplásicas Circulantes/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología
11.
J Biomol Struct Dyn ; : 1-15, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38356140

RESUMEN

Cancer is an aberrant differentiation of normal cells, characterized by uncontrolled growth and the potential to acquire invasive and aggressive properties that ultimately lead to metastasis. In the realm of scientific exploration, a multitude of pathways has been investigated and targeted by researchers, among which one specific pathway is recognized as WDR5-MYC. Continuous investigations and research show that WDR5-MYC is a therapeutic target protein. Hence, the discovery of naturally occurring compounds with anticancer properties has been suggested as a rapid and efficient alternative for the development of anticancerous therapeutics. A virtual screening approach was used to identify the most potent compounds from the NP-lib database at the MTiOpenScreen webserver against WDR5-MYC. This process yielded a total of 304 identified compounds. Subsequently, after screening, four potent compounds, namely Estrone (ZINC000003869899), Ethyl-1,2-benzanthracene (ZINC000003157052), Strychnine (ZINC000000119434) and 7H-DIBENZO [C, G] CARBAZOLE (ZINC000001562130), along with a cocrystallized 5-[4-(trifluoromethyl) phenyl]-1H-tetrazole inhibitor (QBP) as a reference ligand, were considered for stringent molecular docking. Thus, each compound exhibited significant docking energy between -8.2 and -7.7 kcal/mol and molecular contacts with essential residue Asn225, Lys250, Ser267 and Lys272 in the active pocket of WDR5-MYC against the QBP inhibitor (the native ligand QBP serves as a reference in the comparative analysis of docked complexes). The results support the potent compounds for drug-likeness and strong binding affinity with WDR5-MYC protein. Further, the stability of the selected compounds was predicted by molecular dynamics simulation (100 ns) contributed by intermolecular hydrogen bonds and hydrophobic interactions. This demonstrates the potential of the selected compounds to be used against breast cancer treatment.Communicated by Ramaswamy H. Sarma.

12.
Heliyon ; 10(7): e28457, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38586388

RESUMEN

ß-carotene is obtained from both plants and animals and has been the subject of intense research because of its provitamin-A, antioxidant, and anticancer effects. Its limited absorption and oxidative degradation significantly reduce its antitumor efficacy when taken orally. In our study, we utilize a central composite design to develop "bio-safe and highly bio-compatible" solid lipid nanoparticles (SLNs) by using only the combination of palmitic acid and poloxamer-407, a block co-polymer as a surfactant. The current research aim to develop and characterize SLNs loaded with ß-carotene to improve their bioavailability and therapeutic efficacy. In addition, the improved cytotoxicity of solid lipid nanoparticles loaded with ß-carotene was screened in-vitro in human breast cancer cell lines (MCF-7). The nanoparticles exhibits good stability, as indicated by their mean zeta potential of -26.3 ± 1.3 mV. The particles demonstrated high drug loading and entrapment capabilities. The fabricated nanoparticle's prolonged release potential was shown by the in-vitro release kinetics, which showed a first-order release pattern that adhered to the Higuchi model and showed a slow, linear, and steady release over 48 h. Moreover, a diffusion-type release mechanism was used to liberate ß-carotene from the nanoparticles. For six months, the nanoparticles also showed a notable degree of physical stability. Lastly, using the MTT assay, the anti-cancer properties of ß-carotene-loaded solid lipid nanoparticles were compared with intact ß-carotene on MCF-7 cell lines. The cytotoxicity tests have shown that the encapsulation of ß-carotene in the lipid bilayers of the optimized formulation does not interfere with the anti-cancer activity of the drug. When compared to standard ß-carotene, ß-carotene loaded SLNs showed enhanced anticancer efficacy and it is a plausible therapeutic candidate for enhancing the solubility of water-insoluble and degradation-sensitive biotherapeutics like ß-carotene.

13.
Clin Cancer Res ; 30(2): 420-435, 2024 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-37611074

RESUMEN

PURPOSE: Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can sensitize intracranial tumors to programmed cell death protein 1 (PD-1) inhibition in mouse models of melanoma and breast cancer brain metastasis. EXPERIMENTAL DESIGN: Treatment response was evaluated in vivo using immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial tumors. Treatment effect on intracranial and extracranial tumor-immune microenvironments (TIME) was evaluated using immunofluorescence, multiplex immunoassays, high-parameter flow cytometry, and T-cell receptor profiling. Mice with humanized immune systems were evaluated using flow cytometry to study the effect of CDKi on human T-cell development. RESULTS: We found that combining abemaciclib with PD-1 inhibition reduced tumor burden and improved overall survival in mice. The TIME, which differed on the basis of anatomic location of tumors, was altered with CDKi and PD-1 inhibition in an organ-specific manner. Combination abemaciclib and anti-PD-1 treatment increased recruitment and expansion of CD8+ effector T-cell subsets, depleted CD4+ regulatory T (Treg) cells, and reduced levels of immunosuppressive cytokines in intracranial tumors. In immunodeficient mice engrafted with human immune systems, abemaciclib treatment supported development and maintenance of CD8+ T cells and depleted Treg cells. CONCLUSIONS: Our results highlight the distinct properties of intracranial and extracranial tumors and support clinical investigation of combination CDK4/6 and PD-1 inhibition in patients with brain metastases. See related commentary by Margolin, p. 257.


Asunto(s)
Neoplasias Encefálicas , Receptor de Muerte Celular Programada 1 , Humanos , Ratones , Animales , Neoplasias Encefálicas/patología , Aminopiridinas/farmacología , Aminopiridinas/uso terapéutico , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Linfocitos T CD8-positivos , Microambiente Tumoral , Quinasa 4 Dependiente de la Ciclina/metabolismo
14.
Microrna ; 12(2): 114-130, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37638608

RESUMEN

Being an integral part of the eukaryotic transcriptome, miRNAs are regarded as vital regulators of diverse developmental and physiological processes. Clearly, miRNA activity is kept in check by various regulatory mechanisms that control their biogenesis and decay pathways. With the increasing technical depth of RNA profiling technologies, novel insights have unravelled the spatial diversity exhibited by miRNAs inside a cell. Compartmentalization of miRNAs adds complexity to the regulatory circuits of miRNA expression, thereby providing superior control over the miRNA function. This review provides a bird's eye view of miRNAs expressed in different subcellular locations, thus affecting the gene regulatory pathways therein. Occurrence of miRNAs in diverse intracellular locales also reveals various unconventional roles played by miRNAs in different cellular organelles and expands the scope of miRNA functions beyond their traditionally known repressive activities.


Asunto(s)
MicroARNs , MicroARNs/genética , Transcriptoma
15.
Eur J Pharmacol ; 946: 175648, 2023 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-36894049

RESUMEN

Depression is the most common mental health disorder worldwide; however, the exact cellular and molecular mechanisms of this major depressive disorder are unclear so far. Experimental studies have demonstrated that depression is associated with significant cognitive impairment, dendrite spine loss, and reduction in connectivity among neurons that contribute to symptoms associated with mood disorders. Rho/Rho-associated coiled-coil containing protein kinase (ROCK) receptors are exclusively expressed in the brain and Rho/ROCK signaling has gained considerable attention as it plays a crucial role in the development of neuronal architecture and structural plasticity. Chronic stress-induced activation of the Rho/ROCK signaling pathway promotes neuronal apoptosis and loss of neural processes and synapses. Interestingly, accumulated evidence has identified Rho/ROCK signaling pathways as a putative target for treating neurological disorders. Furthermore, inhibition of the Rho/ROCK signaling pathway has proven to be effective in different models of depression, which signify the potential benefits of clinical Rho/ROCK inhibition. The ROCK inhibitors extensively modulate antidepressant-related pathways which significantly control the synthesis of proteins, and neuron survival and ultimately led to the enhancement of synaptogenesis, connectivity, and improvement in behavior. Therefore, the present review refines the prevailing contribution of this signaling pathway in depression and highlighted preclinical shreds of evidence for employing ROCK inhibitors as disease-modifying targets along with possible underlying mechanisms in stress-associated depression.


Asunto(s)
Trastorno Depresivo Mayor , Enfermedades del Sistema Nervioso , Humanos , Depresión/tratamiento farmacológico , Neuronas , Transducción de Señal , Quinasas Asociadas a rho
16.
Curr Cancer Drug Targets ; 23(8): 620-633, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36843367

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is one of the foremost causes of cancer-related morbidities worldwide. Novel nanotechnology-backed drug delivery stratagems, including molecular targeting of the chemotherapeutic payload, have been considered. However, no quantum leap in the gross survival rate of patients with PDAC has been realized. One of the predominant causes behind this is tumor desmoplasia, a dense and heterogenous stromal extracellular matrix of the tumor, aptly termed tumor microenvironment (TME). It plays a pivotal role in the tumor pathogenesis of PDAC as it occupies most of the tumor mass, making PDAC one of the most stromal-rich cancers. The complex crosstalk between the tumor and dynamic components of the TME impacts tumor progression and poses a potential barrier to drug delivery. Understanding and deciphering the complex cascade of tumorstromal interactions are the need of the hour so that we can develop neoteric nano-carriers to disrupt the stroma and target the tumor. Nanodiamonds (NDs), due to their unique surface characteristics, have emerged as a promising nano delivery system in various pre-clinical cancer models and have the potential to deliver the chemotherapeutic payload by moving beyond the dynamic tumor-stromal barrier. It can be the next revolution in nanoparticle-mediated pancreatic cancer targeting.


Asunto(s)
Carcinoma Ductal Pancreático , Nanodiamantes , Neoplasias Pancreáticas , Humanos , Nanodiamantes/uso terapéutico , Terapia Molecular Dirigida , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Microambiente Tumoral , Neoplasias Pancreáticas
17.
Front Genet ; 14: 1248697, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37609038

RESUMEN

Maize serves as a crucial nutrient reservoir for a significant portion of the global population. However, to effectively address the growing world population's hidden hunger, it is essential to focus on two key aspects: biofortification of maize and improving its yield potential through advanced breeding techniques. Moreover, the coordination of multiple targets within a single breeding program poses a complex challenge. This study compiled mapping studies conducted over the past decade, identifying quantitative trait loci associated with grain quality and yield related traits in maize. Meta-QTL analysis of 2,974 QTLs for 169 component traits (associated with quality and yield related traits) revealed 68 MQTLs across different genetic backgrounds and environments. Most of these MQTLs were further validated using the data from genome-wide association studies (GWAS). Further, ten MQTLs, referred to as breeding-friendly MQTLs (BF-MQTLs), with a significant phenotypic variation explained over 10% and confidence interval less than 2 Mb, were shortlisted. BF-MQTLs were further used to identify potential candidate genes, including 59 genes encoding important proteins/products involved in essential metabolic pathways. Five BF-MQTLs associated with both quality and yield traits were also recommended to be utilized in future breeding programs. Synteny analysis with wheat and rice genomes revealed conserved regions across the genomes, indicating these hotspot regions as validated targets for developing biofortified, high-yielding maize varieties in future breeding programs. After validation, the identified candidate genes can also be utilized to effectively model the plant architecture and enhance desirable quality traits through various approaches such as marker-assisted breeding, genetic engineering, and genome editing.

18.
Expert Opin Ther Pat ; 33(10): 681-699, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37991186

RESUMEN

INTRODUCTION: Nanotechnology may open up new avenues for overcoming the challenges of pancreatic cancer therapy as a broad arsenal of anticancer medicines fail to realize their full therapeutic potential in pancreatic ductal adenocarcinoma due to the formation of multiple resistance mechanisms inside the tumor. Many studies have reported the successful use of various nano formulations in pancreatic cancer therapy. AREAS COVERED: This review covers all the major nanotechnology-based patent litrature available on renowned patent data bases like Patentscope and Espacenet, through the time period of 2007-2022. This is an entirely patent centric review, and it includes both clinical and non-clinical data available on nanotechnology-based therapeutics and diagnostic tools for pancreatic cancer. EXPERT OPINION: For the sake of understanding, the patents are categorized under various formulation-specific heads like metallic/non-metallic nanoparticles, polymeric nanoparticles, liposomes, carbon nanotubes, protein nanoparticles and liposomes. This distinguishes one specific nanoparticle type from another and makes this review a one-of-a-kind comprehensive patent compilation that has not been reported so far in the history of nanotechnological formulations in pancreatic cancer.


Asunto(s)
Nanopartículas , Nanotubos de Carbono , Neoplasias Pancreáticas , Humanos , Liposomas/uso terapéutico , Sistemas de Liberación de Medicamentos , Patentes como Asunto , Nanotecnología , Neoplasias Pancreáticas/tratamiento farmacológico
19.
Ther Deliv ; 14(9): 543-569, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37671556

RESUMEN

Atopic dermatitis is a prevalent chronic skin inflammation affecting 2.1 to 4.1% of adults globally. The complexity of its pathogenesis and the relapsing nature make it challenging to treat. Current treatments follow European Academy of Dermatology and Venerology guidelines, but advanced cases with recurring lesions lack effective therapies. To address this gap, researchers are exploring nanotechnology for targeted drug delivery. Nanoparticles offer benefits such as improved drug retention, stability, controlled release and targeted delivery through the disrupted epidermal barrier. This integrated review evaluates the current state of AD treatment and highlights the potential of novel nano-formulations as a promising approach to address the disease.


Atopic dermatitis is a skin disease and difficult to treat. It happens because of various reasons like skin barrier problems, weather conditions, irritants and allergens from microorganisms. The current treatments do not fully cure the disease, and there's no established treatment for it but there is hope in nanotechnology and nanoformulations. Nano formulations are preparations with particles between 8 and 250 nm. Moreover, studies with animals and humans show promising results with nanoformulations. This review paper explores different ways to use nanotechnology to treat atopic dermatitis. It might lead to exciting new treatments in the future.


Asunto(s)
Dermatitis Atópica , Adulto , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/etiología , Dermatitis Atópica/patología , Inflamación/tratamiento farmacológico , Epidermis , Sistemas de Liberación de Medicamentos , Nanotecnología
20.
ACS Omega ; 8(45): 43151-43162, 2023 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-38024765

RESUMEN

Myo-inositol hexakisphosphates (IHPs) or phytates are the most abundant organic phosphates having the potential to serve as a phosphorus reserve in soil. Understanding the fate of IHP interaction with soil minerals tends to be crucial for its efficient storage and utilization as a slow-release organic phosphate fertilizer. We have systematically compared the effective intercalation strategy of a phytate onto Zn-Fe layered double hydroxide (LDH) acting as storage/carrier material through coprecipitation and anion exchange. Powder X-ray diffraction, X-ray photoelectron spectroscopy, elemental analysis, thermogravimetric analysis, FTIR spectra, and molecular modeling demonstrated the formation of phytate-intercalated Zn-Fe LDH through coprecipitation with a maximum loading of 41.34% (w/w) in the pH range of ∼9-10 in a vertical alignment through monolayer formation. No intercalation product was obtained from the anion exchange method, which was concluded based on the absence of shifting in the XRD (003) peak. A change in the zeta potential values from positive to negative and subsequent increase in solution pH, with decreasing phytate concentration, are suggestive of adsorption of IHP onto the LDH surface. The batch adsorption data were best fitted with Langmuir isotherm equation and followed the pseudo-second-order kinetic model. The maximum adsorption capacity was found to be 45.87 mg g-1 at a temperature of 25 ± 0.5 °C and pH 5.63.

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