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The management of metastatic cancer is complicated by chemotherapy resistance. This manuscript provides a comprehensive academic review of strategies to overcome chemotherapy resistance in metastatic cancer. The manuscript presents background information on chemotherapy resistance in metastatic cancer cells, highlighting its clinical significance and the current challenges associated with using chemotherapy to treat metastatic cancer. The manuscript delves into the molecular mechanisms underlying chemotherapy resistance in subsequent sections. It discusses the genetic alterations, mutations, and epigenetic modifications that contribute to the development of resistance. Additionally, the role of altered drug metabolism and efflux mechanisms, as well as the activation of survival pathways and evasion of cell death, are explored in detail. The strategies to overcome chemotherapy resistance are thoroughly examined, covering various approaches that have shown promise. These include combination therapy approaches, targeted therapies, immunotherapeutic strategies, and the repurposing of existing drugs. Each strategy is discussed in terms of its rationale and potential effectiveness. Strategies for early detection and monitoring of chemotherapy drug resistance, rational drug design vis-a-vis personalized medicine approaches, the role of predictive biomarkers in guiding treatment decisions, and the importance of lifestyle modifications and supportive therapies in improving treatment outcomes are discussed. Lastly, the manuscript outlines the clinical implications of the discussed strategies. It provides insights into ongoing clinical trials and emerging therapies that address chemotherapy resistance in metastatic cancer cells. The manuscript also explores the challenges and opportunities in translating laboratory findings into clinical practice and identifies potential future directions and novel therapeutic avenues. This comprehensive review provides a detailed analysis of strategies to overcome chemotherapy resistance in metastatic cancer. It emphasizes the importance of understanding the molecular mechanisms underlying resistance and presents a range of approaches for addressing this critical issue in treating metastatic cancer.
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Cancer whose major problems are metastasis, treatment resistance, and recurrence is the leading cause of death worldwide. Tumor-initiating stem cells (TiSCs) are a subset of the tumor population responsible for tumor resistance and relapse. Understanding the characteristics and shared features between tumor-initiating stem cells (TiSCs) and long-lived postmitotic cells may hold a key to better understanding the biology of cancer. Postmitotic cells have exited the cell cycle and are transitioned into a non-dividing and terminally differentiated state with a specialized function within a tissue. Conversely, a cancer cell with TiSC feature can divide and produce a variety of progenies, and is responsible for disease progression, tumor resistance to therapy and immune system and disease relapse. Surprisingly, our comprehensive evaluation of TiSCs suggests common features with long-lived post-mitotic cells. They are similar in structure (primary cilia, high mitochondrial content, and being protected by a barrier), metabolism (autophagy and senescence), and function (immunoescape and/or immune-privileged by a blood barrier). In-depth exploration showed how mitochondrial metabolism contributes to these shared features, including high energy demands arising from ciliary and microtubular functionality, increased metabolic activity, and movement. These findings can assist in decoding the remaining properties which offer insights into the biology of TiSCs, with potential implications for enhancing cancer treatment strategies and patient prognosis.
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Neoplasias , Humanos , Neoplasias/metabolismo , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/patologia , Diferenciação Celular , Recidiva , Microambiente TumoralRESUMO
Energy is needed by cancer cells to stay alive and communicate with their surroundings. The primary organelles for cellular metabolism and energy synthesis are mitochondria. Researchers recently proved that cancer cells can steal immune cells' mitochondria using nanoscale tubes. This finding demonstrates the dependence of cancer cells on normal cells for their living and function. It also denotes the importance of mitochondria in cancer cells' biology. Emerging evidence has demonstrated how mitochondria are essential for cancer cells to survive in the harsh tumor microenvironments, evade the immune system, obtain more aggressive features, and resist treatments. For instance, functional mitochondria can improve cancer resistance against radiotherapy by scavenging the released reactive oxygen species. Therefore, targeting mitochondria can potentially enhance oncological outcomes, according to this notion. The tumors' responses to anticancer treatments vary, ranging from a complete response to even cancer progression during treatment. Therefore, personalized cancer treatment is of crucial importance. So far, personalized cancer treatment has been based on genomic analysis. Evidence shows that tumors with high mitochondrial content are more resistant to treatment. This paper illustrates how mitochondrial metabolism can participate in cancer resistance to chemotherapy, immunotherapy, and radiotherapy. Pretreatment evaluation of mitochondrial metabolism can provide additional information to genomic analysis and can help to improve personalized oncological treatments. This article outlines the importance of mitochondrial metabolism in cancer biology and personalized treatments.
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Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the dependence on the normal cells. This article illustrates the benefits of new functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells' survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in the metabolism of cancer stem cells (CSCs), the tumor components responsible for cancer recurrence and metastasis. This theory highlights the mitochondria in cancer biology and explains how targeting mitochondria may improve oncological outcomes.
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Mitocôndrias , Neoplasias , Humanos , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias/patologia , Microambiente TumoralRESUMO
Citrullinemia type 1 is an autosomal recessive metabolic disease caused by ASS1 gene mutations encoding argininosuccinic acid synthetase enzyme which is within the pathway of arginine and nitric oxide biosynthesis. Disease confirmation was done by ASS1 gene mutation analysis using next-generation sequencing, DNA Sanger sequencing. The study group was 17 citrullinemia type 1 patients from 10 unrelated families referred to Iranian National Society for Study on Inborn Errors of Metabolism's clinic between 2008 and 2020. Clinical, laboratory, and molecular data were retrospectively evaluated. Eleven different ASS1 gene mutations were detected in 13 (76%) of 17 neonatal, three (18%) of 17 late infantile, and one (6%) of 17 asymptomatic patients. Severe developmental delay and intractable seizures despite metabolic control was outcome of neonatal form survivor. Two late infantile form patients live metabolically controlled with quite normal performance. DNA mutations are as follows: seven missense, one nonsense, and two insertion/deletion mutations in 12, two, and three patients, respectively. Five novel mutations were detected including a homozygous GG deletion in exon 12 (c.790_791delGG;p.Gly264Profs*3) and a homozygous mutation in exon 7 (c.440C>T; p.Met147Thr), both causing infantile (late onset) form; a homozygous mutation in exon 6 (c.1130T>C; p.Met376Thr) causing neonatal form; two compound heterozygote mutations in exon 14 (c.1167_1168insC:p.Gly390Argfs*22& c.1186T>A; p.Ser396Thr) causing asymptomatic form. Five (38%) patients with classic neonatal form had mutation in exon 14 of ASS1 (c.1168G>A; p.Gly390Arg). Classic neonatal was the most common form of disease in Iranian-studied patients and homozygote c.1168G>A was the most frequent ASS1 gene mutation. Global neonatal screening for citrullinemia type 1 in Iran is recommended and certain mutations can be used for screening severe form in this population.
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KEY MESSAGE: We characterized genes that function in the photoperiodic flowering pathway in cassava. Transcriptome analysis of field-grown plants revealed characteristic expression patterns of these genes, demonstrating that field-grown cassava experiences two distinct developmental transitions. Cassava is an important crop for both edible and industrial purposes. Cassava develops storage roots that accumulate starch, providing an important source of staple food in tropical regions. To facilitate cassava breeding, it is important to elucidate how flowering is controlled. Several important genes that control flowering time have been identified in model plants; however, comprehensive characterization of these genes in cassava is still lacking. In this study, we identified genes encoding central flowering time regulators and examined these sequences for the presence or absence of conserved motifs. We found that cassava shares conserved genes for the photoperiodic flowering pathway, including florigen, anti-florigen and its associated transcription factor (GIGANTEA, CONSTANS, FLOWERING LOCUS T, CENTRORADIALIS/TERMINAL FLOWER1 and FD) and florigen downstream genes (SUPRESSOR OF OVEREXPRESSION OF CONSTANS1 and APETALA1/FRUITFUL). We conducted RNA-seq analysis of field-grown cassava plants and characterized the expression of flowering control genes. Finally, from the transcriptome analysis we identified two distinct developmental transitions that occur in field-grown cassava.
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Flores/crescimento & desenvolvimento , Flores/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica de Plantas/genética , Manihot/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Colômbia , Florígeno/antagonistas & inibidores , Florígeno/metabolismo , Flores/genética , Perfilação da Expressão Gênica , Manihot/genética , Manihot/crescimento & desenvolvimento , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Alinhamento de SequênciaRESUMO
BACKGROUND: Chronic rhinosinusitis (CRS) describes an inflammatory condition affecting the sinonasal mucosa. As the immune system players such as immunoglobulins play prominent roles in the development of CRS, we aimed to investigate the expression of IgA subclasses and factors involved in IgA class switching in the sinonasal mucosa of CRS patients. METHODS: Specimens were collected from the sinonasal mucosa of the healthy controls and CRS patients. Histological assessments were performed by H&E and immunohistochemistry. Real-time PCR and ELISA methods were applied to measure gene expression and protein levels extracted from tissue samples, respectively. RESULTS: We observed that total IgA and subclass-positive cells were higher in the patient groups than controls. There was a significant correlation between the number of eosinophils and total IgA and subclasses-positive cells (Pv < 0.0001). The expression of CXCL13, BAFF, AID, and germline transcripts were increased in CRSwNP patients. In contrast to IgA2 levels, IgA1 levels were significantly increased in the sinonasal tissue of CRSwNP patients (Pv < 0.01). TGF-ß was significantly elevated in the sinonasal tissue of patients with CRSsNP. CONCLUSIONS: Increased protein levels of IgA subclasses and related antibody-producing cells were associated with elevated eosinophils in CRSwNP patients which may result in eosinophil pathological functions. Several therapeutic approaches might be developed to modulate the IgA production to ameliorate the inflammatory mechanisms in CRSwNP patients.
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We developed and modified a precise, rapid, and reproducible protocol isolating high-quality RNA from tissues of multiple varieties of cassava plants (Manihot esculenta Crantz). The resulting method is suitable for use in mini, midi, and maxi preparations and rapidly achieves high total RNA yields (170-600 µg·g-1) using low-cost chemicals and consumables and with minimal contamination from polysaccharides, polyphenols, proteins, and other secondary metabolites. In particular, A260 : A280 ratios were > 2.0 for RNA from various tissues, and all of the present RNA samples yielded ribosomal integrity number values of greater than six. The resulting high purity and quality of isolated RNA will facilitate downstream applications (quantitative reverse transcriptase-polymerase chain reaction or RNA sequencing) in cassava molecular breeding.
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Perfilação da Expressão Gênica/métodos , Manihot/genética , RNA de Plantas/isolamento & purificação , Perfilação da Expressão Gênica/instrumentação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNARESUMO
Attention has been focused on the field of genetics and genomics in Iran in recent years and some efforts have been enforced and implemented. However, they are totally not adequate, considering the advances in medical genetics and genomics in the past two decades around the world. Overall, considering the lack of medical genetics residency programs in the Iranian health education system, big demand due to high consanguinity and intraethnic marriages, there is a lag in genetic services and necessity to an immediate response to fill this big gap in Iran. As clarified in the National constitution fundamental law and re-emphasized in the 6th National Development Plan, the Iranian government authority is in charge of providing the standard level of health including genetic services to all Iranian individuals who are in need.
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Utilização de Instalações e Serviços , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/estatística & dados numéricos , Genética Médica/estatística & dados numéricos , Diagnóstico Pré-Natal/estatística & dados numéricos , Análise de Sequência de DNA/estatística & dados numéricos , Bases de Dados Genéticas , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Testes Genéticos/economia , Testes Genéticos/legislação & jurisprudência , Genética Médica/economia , Genética Médica/legislação & jurisprudência , Genética Médica/organização & administração , Humanos , Irã (Geográfico) , Diagnóstico Pré-Natal/economia , Análise de Sequência de DNA/economiaRESUMO
CLN6 is a transmembrane protein located in the endoplasmic reticulum that is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis (LINCL), and teenage and adult onset NCL without visual impairment. Here we describe two pediatric patients with LINCL from unrelated families who were evaluated at the National Institutes of Health. Both children exhibited typical phenotypes associated with LINCL except that they lacked the expected visual impairment. Whole exome sequencing identified novel biallelic mutations in CLN6, i.e., c.218-220dupGGT (p.Trp73dup) and c.296Aâ¯>â¯G (p.Lys99Arg) in Proband 1 and homozygous c.723Gâ¯>â¯T (p.Met241Ile) in Proband 2. Expression analysis in dermal fibroblasts showed a small increase in CLN6 protein levels. Electron micrographs of these fibroblasts demonstrated large numbers of small membrane-bound vesicles, in addition to lipofuscin deposits. LysoTracker™ Red intensity was increased in fibroblasts from both patients. This study supports a role for CLN6 in lysosomal homeostasis, and highlights the importance of considering CLN6 mutations in the diagnosis of Batten Disease even in patients with normal vision.
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Proteínas de Membrana/genética , Mutação , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/genética , Adolescente , Adulto , Criança , Exoma/genética , Feminino , Fibroblastos/química , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , National Institutes of Health (U.S.) , Linhagem , Estados Unidos , Transtornos da VisãoRESUMO
BACKGROUND: Some male survivors of childhood cancer are suffering from azoospermia. In addition, spermatogonial stem cells (SSCs) are necessary for the improvement of spermatogenesis subsequent to exposure to cytotoxic agents such as cisplatin. OBJECTIVE: The aim of this study was to evaluate the anticancer activity of cisplatin-loaded folic acid-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) on mouse malignant cell line (EL4) and SSCs in vitro. METHODS: SSCs were co-cultured with mouse malignant cell line (EL4) cells and divided into four culture groups: 1) control (cells were co-cultured in the culture medium), 2) co-cultured cells were treated with cisplatin (10 µg/mL), 3) co-cultured cells were treated with cisplatin-loaded folic acid-conjugated PLGA NPs, and 4) co-cultures were treated with folic acid-conjugated PLGA for 48 hours. The NPs were prepared, characterized, and targeted with folate. In vitro release characteristics, loading efficiency, and scanning electron microscopy and transmission electron microscopy images were studied. Cancer cells were assayed after treatment using flow cytometry and TUNEL assay. The co-cultures of SSCs and EL4 cells were injected into seminiferous tubules of the testes after treating with cis-diaminedichloroplatinum/PLGA NPs. RESULTS: The mean diameter of PLGA NPs ranged between 150 and 250 nm. The number of TUNEL-positive cells increased, and the expression of Bax and caspase-3 were upregulated in EL4 cells in Group 4 compared with Group 2. There was no pathological tumor in testes after transplantation with treated co-cultured cells. CONCLUSION: The PLGA NPs appeared to act as a promising carrier for cisplatin administration, which was consistent with a higher activation of apoptosis than free drug.
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Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Ácido Fólico/química , Nanopartículas/administração & dosagem , Espermatogônias/patologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Cocultura , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Ácido Fólico/administração & dosagem , Ácido Láctico/química , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/patologia , Espermatogônias/efeitos dos fármacosAssuntos
Distonia/diagnóstico , Fosfolipases A2 do Grupo VI/genética , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Distúrbios do Metabolismo do Ferro/diagnóstico , Distrofias Neuroaxonais/diagnóstico , Adulto , Consanguinidade , Distonia/etiologia , Distonia/genética , Distonia/fisiopatologia , Olho/fisiopatologia , Transtornos Heredodegenerativos do Sistema Nervoso/complicações , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Humanos , Distúrbios do Metabolismo do Ferro/complicações , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Distrofias Neuroaxonais/complicações , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/fisiopatologia , Torcicolo/fisiopatologia , Adulto JovemRESUMO
Complement C3 glomerulopathy refers to a disease process in which abnormal control of complement activation or degradation results in predominant C3 fragment deposition within the glomerulus and causes glomerular damage. Abnormal control of the complement alternative pathway is a well-established risk factor for the occurrence of C3 glomerulonephritis. It is the first reported case in Iran with multiple mutations in complement factor H, with one of these mutations we have expected in hemolytic uremic syndrome rather than C3 glomerulopathy Genetic analysis showed that the molecular abnormalities of factor H led to complement factor H malfunction that were polymorphous and not restricted to the C-terminal domains of the protein.
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Síndrome Hemolítico-Urêmica Atípica/etiologia , Complemento C3/genética , Glomerulonefrite/genética , Glomérulos Renais/patologia , Adulto , Ativação do Complemento , Fator H do Complemento/deficiência , Fator H do Complemento/genética , Via Alternativa do Complemento , Feminino , Glomerulonefrite/complicações , Glomerulonefrite/patologia , Humanos , Irã (Geográfico) , MutaçãoRESUMO
Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.
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Hérnia Hiatal/genética , Microcefalia/genética , Complexos Multiproteicos/genética , Mutação , Nefrose/genética , Animais , Apoptose/genética , Sistemas CRISPR-Cas , Proteínas de Transporte/genética , Movimento Celular , Citoesqueleto/ultraestrutura , Reparo do DNA/genética , Estresse do Retículo Endoplasmático/genética , Técnicas de Inativação de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metaloendopeptidases/deficiência , Metaloendopeptidases/genética , Camundongos , Modelos Moleculares , Síndrome Nefrótica/genética , Síndrome Nefrótica/patologia , Podócitos/metabolismo , Podócitos/ultraestrutura , Conformação Proteica , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Processamento Pós-Transcricional do RNA/genética , RNA de Transferência/metabolismo , Homeostase do Telômero/genética , Peixe-Zebra , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genéticaRESUMO
PURPOSE: In this report, we document the CTNS gene mutations of 28 Iranian patients with nephropathic cystinosis age 1-17 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. METHODS: Cystinosis was primarily diagnosed by a pediatric nephrologist and then referred to the Iran University of Medical Sciences genetics clinic for consultation and molecular analysis, which involved polymerase chain reaction (PCR) amplification to determine the presence or absence of the 57-kb founder deletion in CTNS, followed by direct sequencing of the coding exons of CTNS. RESULTS: The common 57-kb deletion was not observed in any of the 28 Iranian patients. In 14 of 28 patients (50%), mutations were observed in exons 6 and 7. No mutation was detected in exon 5, and only one (3.6%) patient with cystinosis showed a previously reported 4-bp deletion in exon 3 of CTNS. Four patients (14.3%) had a previously reported mutation (c.969C>A; p.N323K) in exon 11, and five (18%) had novel homozygous deletions in exon 6 leading to premature truncation of the protein. These deletions included c.323delA; p.Q108RfsX10 in three individuals and c.257-258delCT; p.S86FfsX37 in two cases. Other frame-shift mutations were all novel homozygous single base pair deletion/insertions including one in CTNS exon 9 (c.661insT; p.V221CfsX6), and four (14.3%) in exon 4, i.e., c.92insG; p.V31GfsX28 in two and c.120delC; p.T40TfsX10 in two. In total, we identified eight previously reported mutations and eight novel mutations in our patients. The only detected splice site mutation (IVS3-2A>C) was associated with the insertion mutation in the exon 9. CONCLUSION: This study, the first molecular genetic analysis of non-ethnic-specific Iranian nephropathic cystinosis patients, may provide guidance for molecular diagnostics of cystinosis in Iran.
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Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinose/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Irã (Geográfico) , Masculino , MutaçãoRESUMO
We investigated the role of glial cell line-derived neurotrophic factor (GDNF) in compensating trastuzumab (TZMB)-induced apoptosis in HER2+ breast cancer (BC) cells using xenograft tumors. We generated BC xenografts in nude mice using samples from three patients selected based on their HER2 status and response to TZMB therapy. TZMB treatment resulted in shrinkage of the HER2+ TZMB-sensitive xenograft tumor but not the HER2- or HER2+ TZMB-resistant ones. GDNF neutralized TZMB activity and induced growth in all tumors. Three distinct cell lines were derived from these tumors and named, respectively, TZMB-sensitive (TSTC), HER2- (HNTC), and TZMB-resistant (TRTC). Over 50% of TRTC but 1% of TSTC cells expressed CD44, whereas 84% of TSTC were CD24+ compared to only 1% of TRTC, despite comparable levels of HER2 detected in both. TZMB induced profound morphological changes toward apoptosis in TSTC but not in TRTC or HNTC. However, GDNF significantly compensated TZMB-mediated TSTC cell loss and promoted growth by 37 and 50%, respectively, in TSTC and TRTC. Inhibition of SRC by Saracatinib (SARC) blocked GDNF function and accelerated TZMB-mediated cell death in TSTC, but GDNF continued promoting TRTC growth. These changes paralleled with expression levels of the key molecules involved in growth and apoptosis. Collectively, we found in our xenograft samples that firstly SRC mediates GDNF pro-survival functions by bridging RET-HER2 crosstalk in TZMB-responsive BC tumors. Secondly, SARC-TZMB interactions can synergistically eradicate such tumor cells; and thirdly, GDNF can support antibody resistance by acting independent from SRC in tumors with poor HER2 response to TZMB therapy.
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Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Proteínas Proto-Oncogênicas c-ret/metabolismo , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , Quinases da Família src/metabolismo , Animais , Apoptose , Benzodioxóis/farmacologia , Biomarcadores , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Antígeno CD24/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Expressão Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-ret/genética , Quinazolinas/farmacologia , Receptor ErbB-2/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/genéticaRESUMO
BACKGROUND: Although stem cell therapy has become a major focus as a new option for management of spinal cord injury (SCI), its effectiveness should be promoted. In this study, we investigated the effects of co-administrating human adipose-derived stem cells (hADSCs) and Chondroitinase ABC (ChABC) in a rat model of spinal cord injury. MATERIAL AND METHODS: hADSCs derived from superficial layer of abdominal adipose tissue were used to treat a contusion-induced SCI. Animals were randomly allocated to five equal groups including sham (only laminectomy), SCI (SCI+vehicle injection), hADSCs (1×106 hADSCs/10µl intra-spinal injection), ChABC (10µl of 100U/ml ChABC intra-spinal injection injection), and hADSCs+ChABC. Basso, Beattie and Bresnahan tests were used to evaluate locomotor function. 8weeks after treatment, cavity size, myelination, cell differentiation (neuron and astrocyte), and chondroitin sulfate amount were analyzed. RESULTS: hADSC transplanted animals, ChABC injected animals (P<0.001), and hADSC+ChABC treated rats (P<0.001) displayed significant motor improvement compared to SCI group. Combination therapy of hADSCs and ChABC led to greater locomotor recovery compared to using hADSCs (P<0.001) or ChABC (P<0.01) alone. Spinal cords in the combined and single therapy groups had cavities filled with myelinated areas and less chondroitin sulfate content in comparison with the control group (P<0.001). hADSCs expressed GFAP, B III tubulin and Map2. CONCLUSION: Combination therapy with ChABC and hADSCs exhibits more significant functional recovery than single therapy using either. This result may be applicable in selection of the best therapeutic strategy for SCI.
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Diferenciação Celular/efeitos dos fármacos , Condroitina ABC Liase/uso terapêutico , Traumatismos da Medula Espinal/terapia , Transplante de Células-Tronco , Animais , Condroitina ABC Liase/farmacologia , Terapia Combinada , Modelos Animais de Doenças , Humanos , Laminectomia , Masculino , Regeneração Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Resultado do TratamentoRESUMO
Hypermethioninemia may be benign, present as a nonspecific sign of nongenetic conditions such as liver failure and prematurity, or a severe, progressive inborn error of metabolism. Genetic causes of hypermethioninemia include mitochondrial depletion syndromes caused by mutations in the MPV17 and DGUOK genes and deficiencies of cystathionine ß-synthase, methionine adenosyltransferase types I and III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase, citrin, fumarylacetoacetate hydrolase, and adenosine kinase. Here we present a 3-year old girl with a history of poor feeding, irritability, respiratory infections, cholestasis, congenital heart disease, neurodevelopmental delay, hypotonia, sparse hair, facial dysmorphisms, liver dysfunction, severe hypermethioninemia and mild homocystinemia. Genetic analysis of the adenosine kinase (ADK) gene revealed a previously unreported variant (c.479-480 GA>TG) resulting in a stop codon (p.E160X) in ADK. A methionine-restricted diet normalized the liver function test results and improved her hypotonia.
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Uromodulin (UMOD) gene mutation causes autosomal dominant Uromodulin-Associated Kidney Disease (UAKD), which in turn leads to end-stage renal disease. This is the first case report of a family with UAKD caused by a novel de novo mutation (E197X) in the UMOD gene. This case is a 28-year-old man with severely reduced kidney function [1]. No similar case was reported in his family history. This report highlights and reminds the importance of genetic screening in young patients involving kidney dysfunction, as the UAKD and some other kidney genetic diseases may be late-onset.