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The native extracellular matrix (ECM) provides a matrix to hold tissue/organ, defines the cellular fate and function, and retains growth factors. Such a matrix is considered as a most biomimetic scaffold for tissue engineering due to the biochemical and biological components, 3D hierarchical structure, and physicomechanical properties. Several attempts have been performed to decellularize allo- or xeno-graft tissues and used them for bone repairing and regeneration. Decellularized ECM (dECM) technology has been developed to create an in vivo-like microenvironment to promote cell adhesion, growth, and differentiation for tissue repair and regeneration. Decellularization is mediated through physical, chemical, and enzymatic methods. In this review, we describe the recent progress in bone decellularization and their applications as a scaffold, hydrogel, bioink, or particles in bone tissue engineering. Furthermore, we address the native dECM limitations and the potential of non-bone dECM, cell-based ECM, and engineered ECM (eECM) for in vitro osteogenic differentiation and in vivo bone regeneration.
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Engenharia Tecidual , Alicerces Teciduais , Matriz Extracelular Descelularizada , Matriz Extracelular , Osteogênese , TecnologiaRESUMO
Brain is susceptible to oxidative stress due to its increased oxygen consumption and low antioxidant levels. Oxidative stress plays a crucial role in the pathogenesis of various neurological diseases. This review on the role of herbal medicines in the management of brain injury was performed by searching Web of Science, PubMed, Google Scholar, Scopus, and Iran Medex between 1976 to January 2020. The search words contained brain injury, and the total number of publications for the review study was 32. Studies with various medicinal plants such as Acanthopanax senticosus, Bacopa monnieri, carnosol, Cassia mimosoides, Centella asiatica, Crocus sativus, Cuminum cyminum, curcumin, Feronia limonia, Gardenia jasminoides, Ginkgo biloba, Kaempferia parviflora, Mentha longifolia, Nigella sativa, olive, orientin, pomegranate, quercetin, rice bran, Rosa damascena, Thymus vulgaris, Viola odorata, Withania coagulans, Zingiber officinale, and Ziziphus spina-christi show a significant improvement in brain injury. The different mechanisms for improvement in brain injury by these medicinal plants include HIF-1 (hypoxia-inducible factor 1) signaling, free-radical scavenging, reduction of nitric oxide (NO) toxicity and acetylcholine esterase (AChE) activity, decrease of pAkt and its downstream targets, downregulation of the aquaporin-4 (AQP-4) and TLR4/NF-ĸB/TNF-α signal, reduction in malondialdehyde and NO levels, increasing neuronal density in the hippocampus, and inhibition of oxidative stress. In this review, the neuroprotective actions and molecular mechanisms of herbal medicines are evaluated by reviewing available studies.
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Lesões Encefálicas , Preparações de Plantas/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Humanos , Neuroproteção , Estresse Oxidativo , Plantas MedicinaisRESUMO
The oxidant-stress (OS) has an essential role to play in the pathogenesis and progression of many diseases. OS is the outcome when the level of free-radical-formation is increased or protective-antioxidant-mechanisms are compromised. Its value is expected to increase, although its emerging roles have not been conclusive in different studies. The objective of this study was to explore the level of zinc, copper, and antioxidant in response to obesity-related-stress by measuring superoxide-dismutase (SOD) levels as a key antioxidant-enzyme in 706 individuals with/without obesity. Anthropometric/biochemical parameters including total-cholesterol (TC), fasting-blood-glucose, high-density-lipoprotein (HDL), low-density-lipoprotein, and triglycerides were determined. The activity of SOD was measured followed by the measurement of Cu and Zn levels. Obese subjects had a significantly higher level of body mass index (BMI) and TC, while the level of HDL was lower in the obese group, as compared to the related values in control subjects. The level of Zn was significantly decreased in the obese group, while the level of Cu and Cu/Zn ratio increased. Additionally, we observed that the SOD level was less in obese subjects when compared to that in the non-obese subjects. In addition to the complications of high BMI, low level of Zn and SOD in obesity can be considered a risk factor, resulting in a reduced antioxidant response, supporting the need for identifying a suitable treatment option for this group.
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Obesidade/sangue , Superóxido Dismutase/sangue , Zinco/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Cobre/sangue , Feminino , Humanos , Masculino , Fatores de RiscoRESUMO
Introduction: Recognizing the importance of medicinal plants and the absence of specific medications for traumatic brain injury (TBI) treatment, this study was conducted to evaluate the effects of an aqueous extract of Aloe vera on oxidative stress, blood-brain barrier (BBB) permeability, and neurological scores following TBI. Materials and Methods: Adult male rats were categorized into five groups: sham, TBI, vehicle, low-dose Aloe vera (LA), and high-dose Aloe vera (HA). We induced diffuse TBI using the Marmaro model and administered the aqueous Aloe vera leaf extract, as well as vehicle, via intraperitoneal injection half an hour after TBI. Neurological outcomes were assessed both before and several hours after TBI. Additionally, oxidative stress factors were measured 24 hr after TBI, and Evans blue content (a BBB permeability index) was determined 5 hr after TBI in both serum and brain. Results: Both LA and HA reduced the increase in BBB permeability after TBI, with HA having a more pronounced effect than LA. Both Aloe vera doses decreased brain MDA levels, increased brain TAC, and lowered both serum and brain PC levels. The impact of Aloe vera on brain oxidative parameters was more significant than on serum. HA also counteracted the declining effects of TBI on neurological outcomes at 4 and 24 hr post-TBI. Conclusion: This study suggests that Aloe vera extract may reduce BBB permeability and improve neurological outcomes after TBI by decreasing oxidative factors and increasing antioxidant factors.
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Aloe , Barreira Hematoencefálica , Lesões Encefálicas Traumáticas , Estresse Oxidativo , Extratos Vegetais , Folhas de Planta , Animais , Estresse Oxidativo/efeitos dos fármacos , Aloe/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Extratos Vegetais/farmacologia , Masculino , Ratos , Folhas de Planta/química , Ratos Sprague-Dawley , Permeabilidade/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
Objective: The present work examined the anti-metastatic effects of auraptene and their underlying mechanisms of action in U87 Glioblastoma multiforme (GBM) cells. Materials and Methods: To test the hypothesis, cell culture, Matrigel invasion assay, scratch wound healing assay, gelatin zymography assay, qRT-PCR, and western blot experiments were conducted. Results: At sublethal concentrations of 12.5 and 25 µg/ml, auraptene exhibited a significant reduction in cell invasion and migration of U87 cells, as assessed using scratch wound healing and Transwell tests, respectively. The qRT-PCR and zymography experiments demonstrated a significant decrease in both mRNA expression and activities of MMP-2 and MMP-9 following auraptene treatment. Western blot analysis also showed that MMP-2 protein level and phosphorylation of metastasis-related proteins (p-JNK and p-mTOR) decreased in auraptene-treated cells. Molecular docking studies consistently demonstrated that auraptene exhibits a significant affinity towards MMP-2/-9, the ATP binding site of mTOR and JNK1/2/3. Conclusion: Auraptene inhibited the migration and invasion of GBM cells. This inhibitory effect was induced by modulating specific mechanisms, including suppressing MMPs, JNK, and mTOR activities.
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The purpose of this study was to evaluate the effect of female sexual hormones on intestinal and serum cytokines following traumatic brain injury (TBI). Adult female rats were ovariectomized and distributed among the following 9 groups: (i) sham trauma, (ii) TBI (Marmarou's method), (iii) vehicle (dimethylsulfoxide) treated, (iv) estrogen (E2) treated, (v) progesterone (P) treated, (vi) treated with E2+P, (vii) propylpyrazole triol (PPT) treated, (viii) diarylpropionitrile (DPN) treated, and (ix) control. PPT and DPN are estrogen receptor αand ß agonists, respectively. Serum and intestinal levels of interleukin (IL)-1ß were increased by TBI (P < 0.001). The level of intestinal IL-1ß was increased in the group treated with E2 (P < 0.001). There was a reduction in serum IL-1ß (P < 0.01) and an increase in intestinal IL-1ß level (P < 0.001) in the PPT-treated group compared with the vehicle-treated group. TBI reduced serum IL-6 (P < 0.01) and increased intestinal IL-6 (P < 0.001). Serum IL-6 was increased in the group treated with E2 (P < 0.001), P (P < 0.001), E2+P (P < 0.01), and DPN (P < 0.001) after TBI; however, intestinal IL-6 was higher in the E2-treated group compared with the vehicle-treated group (P < 0.01). Intestinal tumor necrosis factor α (TNF-α) was increased by TBI (P < 0.001). Progesterone decreased serum TNF-α (P < 0.01). Intestinal TNF-α in the E2 (P < 0.01), E2+P (P < 0.001), and PPT (P < 0.001) treatment groups was less than in the vehicle-treated group. In conclusion, estrogen influences the intestinal levels of proinflammatory cytokines, in particular TNF-α, mediated through estrogen receptor α.
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Lesões Encefálicas/tratamento farmacológico , Receptor alfa de Estrogênio/agonistas , Terapia de Reposição de Estrogênios , Estrogênios/farmacologia , Mediadores da Inflamação/sangue , Intestinos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue , Animais , Lesões Encefálicas/sangue , Lesões Encefálicas/imunologia , Lesões Encefálicas/metabolismo , Modelos Animais de Doenças , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Feminino , Interleucina-1beta/sangue , Interleucina-6/sangue , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Nitrilas/farmacologia , Ovariectomia , Fenóis , Progesterona/farmacologia , Propionatos/farmacologia , Pirazóis/farmacologia , Ratos , Ratos WistarRESUMO
In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.
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Neoplasias Encefálicas , Diabetes Mellitus Tipo 2 , Glioblastoma , Metformina , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Glioblastoma/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proliferação de Células , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular TumoralRESUMO
OBJECTIVES: Programmed cell death 1 (PD-1) is a member of the CD28/CTLA-4 family of inhibitory immunological checkpoint receptors that's also widely produced by exhausted T lymphocytes in an immunosuppressive tumor microenvironment. PD-1 binds to programmed death ligand (PD-L1) and suppresses anti-cancer activity of T lymphocytes. We examined the current literature on how siRNA delivery systems can be used to target PD-1 and PD-L1, as well as the anti-cancer mechanisms and challenges associated with siRNA molecules. We look at studies that use program death 1 siRNA or program death 1 ligand siRNA to treat cancer. Several databases have been used for this purpose, including NCBI, Scopus, and Google Scholar. KEY FINDINGS: This study looked at several methods for delivering siRNA to immune cells and cancer cells. According to these findings, suppressing PD-1 in T cells increases T lymphocyte activity. PD-L1 suppression in DCs improves antigen presentation and co-stimulatory signals on their surface, resulting in T cell activation. Chemotherapy resistance and cancer cell suppression of T cells are reduced when PD-L1/2 is suppressed in cancer cells. CONCLUSION: The findings of this study indicated that several strategies for siRNA transfection to immune and cancer cells have been evaluated in recent decades, some of which effectively transfect siRNA to target cells, and defined PD-1 siRNA as a promising strategy for cancer treatment.
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Antígeno B7-H1 , Neoplasias , Linhagem Celular Tumoral , Ligantes , Neoplasias/metabolismo , Neoplasias/terapia , Receptor de Morte Celular Programada 1 , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Linfócitos TRESUMO
Objective: The effects of Cinnamomum zeylanicum on oxidative stress imposed by pentylenetetrazole (PTZ) was examined in mice brain tissues. Materials and Methods: Animals were divided into five groups as follows: 1- control group which received saline; 2- PTZ group (100 mg/kg, ip); and groups 3 to 5 which received (100, 200, and 400 mg/kg) of C. zeylanicum for seven days prior to PTZ injection. The latencies of the first minimal clonic seizure (MCS) and the first generalized tonic-clonic seizure (GTCS) and levels of oxidant and antioxidant biomarkers were measured. Results: Treatment with the two higher doses of the extract significantly increased the MCS and GTCS latencies (p<0.05 to p<0.001). Malondialdehyde (MDA) and nitric oxide (NO) levels were increased, but superoxide dismutase (SOD), catalase (CAT), and thiol were decreased in both cortical and hippocampal tissues of the PTZ group compared to the controls (p<0.001). Pretreatment with the two higher doses of C. zeylanicum significantly led to a significant correction in NO, MDA, SOD and CAT levels in the hippocampus and cortex compared to the PTZ group (p<0.05 to p<0.001). Conclusion: Antioxidant and anticonvulsant effects of C. zeylanicum in PTZ-injected animals may suggest its potential therapeutic effect on nervous diseases such as seizures.
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Since the discovery of phosphodiesterase-5 (PDE5) enzyme overexpression in the central nervous system (CNS) malignancies, investigations have explored the potential capacity of current PDE5 inhibitor drugs for repositioning in the treatment of brain tumors, notably glioblastoma multiforme (GBM). It has now been recognized that these drugs increase brain tumors permeability and enhance standard chemotherapeutics effectiveness. More importantly, studies have highlighted the promising antitumor functions of PDE5 inhibitors, e.g., triggering apoptosis, suppressing tumor cell growth and invasion, and reversing tumor microenvironment (TME) immunosuppression in the brain. However, contradictory reports have suggested a pro-oncogenic role for neuronal cyclic guanosine monophosphate (cGMP), indicating the beneficial function of PDE5 in the brain of GBM patients. Unfortunately, due to the inconsistent preclinical findings, only a few clinical trials are evaluating the therapeutic value of PDE5 inhibitors in GBM treatment. Accordingly, additional studies should be conducted to shed light on the precise effect of PDE5 inhibitors in GBM biology regarding the existing molecular heterogeneities among individuals. Here, we highlighted and discussed the previously investigated mechanisms underlying the impacts of PDE5 inhibitors in cancers, focusing on GBM to provide an overview of current knowledge necessary for future studies.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/tratamento farmacológico , GMP Cíclico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Microambiente TumoralRESUMO
There is growing literature on the positive therapeutic potentials of curcumin. Curcumin or diferuloylmethane is a polyphenol obtained from the plant Curcuma longa. Curcumin is widely used in Ayurvedic and Chinese medicine for various conditions. The role of curcumin in thyroid gland disorders has been demonstrated by its effects on various biological pathways, including anti-inflammatory, antioxidant, anti-proliferative, apoptosis, angiogenesis, cell cycle and metastasis. In this paper, we have reviewed the recent literature on curcumin applications for thyroid dysfunction, including hyperthyroidism and hypothyroidism, and discussed the molecular mechanisms of these effects. This review aims to summarize the wealth of research related to the therapeutic effect of curcumin on the thyroid gland.
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Curcumina , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose , Curcumina/farmacologia , Curcumina/uso terapêutico , Humanos , Glândula TireoideRESUMO
The most typical malignant brain tumor, glioblastoma multiforme (GBM), seems to have a grim outcome, despite the intensive multi-modality interventions. Literature suggests that biologically active phytomolecules may exert anticancer properties by regulating several signaling pathways. Berberine, an isoquinoline alkaloid, has various pharmacological applications to combat severe diseases like cancer. Mechanistically, it inhibits cell proliferation and invasion, suppresses tumor angiogenesis, and induces cell apoptosis. The antitumoral effect of berberine in GBM is increasingly recognized. This review sheds new light on the regulatory signaling mechanisms of berberine in various cancers, proposing its potential role as a therapeutic agent for GBM.
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Berberina , Neoplasias Encefálicas , Glioblastoma , Apoptose , Berberina/farmacologia , Berberina/uso terapêutico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Glioblastoma/metabolismo , HumanosRESUMO
The most widespread, malignant, and deadliest type of glial tumor is glioblastoma multiforme (GBM). Despite radiation, chemotherapy, and radical surgery, the median survival of afflicted individuals is about 12 months. Unfortunately, existing therapeutic interventions are abysmal. Dexamethasone (Dex), a synthetic glucocorticoid, has been used for many years to treat brain edema and inflammation caused by GBM. Several investigations have recently shown that Dex also exerts antitumoral effects against GBM. On the other hand, more recent disputed findings have questioned the long-held dogma of Dex treatment for GBM. Unfortunately, steroids are associated with various undesirable side effects, including severe immunosuppression and metabolic changes like hyperglycemia, which may impair the survival of GBM patients. Current ideas and concerns about Dex's effects on GBM cerebral edema, cell proliferation, migration, and its clinical outcomes were investigated in this study.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/patologia , Proliferação de Células , Dexametasona/uso terapêutico , Glioblastoma/patologia , HumanosRESUMO
Despite conventional treatment options including chemoradiation, patients with the most aggressive primary brain tumor, glioblastoma multiforme (GBM), experience an average survival time of less than 15 months. Regarding the malignant nature of GBM, extensive research and discovery of novel treatments are urgently required to improve the patients' prognosis. Autophagy, a crucial physiological pathway for the degradation and recycling of cell components, is one of the exciting targets of GBM studies. Interventions aimed at autophagy activation or inhibition have been explored as potential GBM therapeutics. This review, which delves into therapeutic techniques to block or activate autophagy in preclinical and clinical research, aims to expand our understanding of available therapies battling GBM.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , AutofagiaRESUMO
Background and purpose: Ferula gummosa (F. gummosa), a potent medicinal herb, has been shown to possess anticancer activities in vitro. The present examination evaluated the cytotoxic and apoptogenic impacts of F. gummosa gum on the U87 glioblastoma cells. Experimental approach: MTT assay to determine the cell viability, flow cytometry by annexin V/FITC-PI to apoptosis evaluation, reactive oxygen species (ROS) assay, and quantitative RT-PCR were performed. Findings / Results: The results revealed that F. gummosa inhibited the growth of U87 cells in a concentration- and time-dependent manner with IC50 values of 115, 82, and 52 µg/mL obtained for 24, 48, and 72 h post-treatment, respectively. It was also identified that ROS levels significantly decreased following 4, 12, and 24 h after treatment. The outcomes of flow cytometry analysis suggested that F. gummosa induced a sub-G1 peak which translated to apoptosis in a concentration-dependent manner. Further examination revealed that F. gummosa upregulated Bax/Bcl-2 ratio and p53 genes at mRNA levels. Conclusion and implications: Collectively, these findings indicate that sub-G1 apoptosis and its related genes may participate in the cytotoxicity of F. gummosa gum in U87 cells.
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ABSTRACT: Type 1 diabetes is an autoimmune disease, and its incidence is usually estimated in the range of 5% to 10%. Currently, the administration of exogenous insulin is the standard of care therapy. However, this therapy is not effective in some patients who may develop some chronic complications. Islet transplantation into the liver is another therapy with promising outcomes; however, the long-term efficacy of this therapeutic option is limited to a small number of patients. Because native extracellular matrix (ECM) components provide a suitable microenvironment for islet functions, engineering a 3-dimensional construct that recapitulates the native pancreatic environment could address these obstacles. Many attempts have been conducted to mimic an in vivo microenvironment to increase the survival of islets or islet-like clusters. With the advent of decellularization technology, it is possible to use a native ECM in organ engineering. Pancreatic decellularized bioscaffold provides proper cell-cell and cell-ECM interactions and retains growth factors that are critical in the determination of cell fate within a native organ. This review summarizes the current knowledge of decellularized matrix technology and addresses its possible limitations before use in the clinic.
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Matriz Extracelular/metabolismo , Pâncreas/metabolismo , Engenharia Tecidual/métodos , Alicerces Teciduais , Microambiente Tumoral , Animais , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Transplante das Ilhotas Pancreáticas/métodos , Pâncreas/citologiaRESUMO
AIM: Traumatic Brain Injury (TBI) is widely acknowledged as a significant risk factor for death and disability. Our goal in this experiment was to see if Auraptene (AUR) could help rats recover from TBI-induced disability by measuring of oxidative stress parameters. MATERIAL AND METHODS: Adult male Wistar rats were randomly assigned to one of six groups: sham, TBI, Vehicle (DMSO), TBI+ AUR (4â¯mg/kg), TBI + AUR (8â¯mg/kg), TBI + AUR (25â¯mg/kg). The animals were anesthetized. After that, diffuse TBI was done by Marmarou model in male rats. Then, the brain tissues were harvested. Some of oxidative stress parameters, and TNFα levels were evaluated. RESULTS: TBI-induced brain damage was significantly inhibited by AUR (25â¯mg/kg), as evidenced by decreased Malondialdehyde (MDA) and Nitric Oxide (NO) levels, oxidative stress inhibition and reduced levels of pro-inflammatory cytokine tumor necrosis factor (TNF-α) in the brain. CONCLUSION: This study showed that probably the AUR prevents complications of TBI through decreases in brain edema, modulating oxidative stress, and reductions in the levels of inflammatory cytokines.
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Lesões Encefálicas Traumáticas , Fármacos Neuroprotetores , Animais , Encéfalo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Cumarínicos , Masculino , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Ratos , Ratos WistarRESUMO
The most widespread and challenging aggressive malignant tumor in the brain is glioblastoma multiforme (GBM). GBM is characterized, in particular, by significant intratumor cell variability, high growth rates, and widespread invasiveness within the surrounding normal brain parenchyma. The present study aimed to examine the impact of the natural product Zerumbone, a promising sesquiterpenoid phytochemical from Zingiber zerumbet, on U-87 MG GBM cells and its underlying molecular mechanisms. At sub-lethal doses, Zerumbone exerted a concentration- and time-dependent suppression of cell migration ability utilizing scratch wound closure assay; it also inhibited GBM cells' invasion using Transwell invasion assay in a concentration-dependent fashion. The enzymatic activity of matrix metalloproteinase (MMP)-2/-9 and their protein expression has also been reduced by administration of Zerumbone. Furthermore, Zerumbone was revealed to downregulate the mRNA expression level of IL-1ß and MCP-1, two genes contributing to MMPs expression. We also found that Zerumbone exerted an inhibitory effect on the expression of Akt and total p44/42 MAPK (Erk1/Erk2) against U-87 MG cells. These findings collectively provide further proof for the possible molecular signaling basis of the antimetastatic effects of Zerumbone as a promising phytochemical, indicating a therapeutic strategy for the treatment of GBM through repression of migration, invasion, and metastasis.
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Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Sesquiterpenos/farmacologia , Neoplasias Encefálicas/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Zingiber officinale , Glioblastoma/metabolismo , Humanos , Invasividade Neoplásica , Sesquiterpenos/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: Based on anti-inflammatory effects of Aloe vera, the effect of aqueous extract of this plant on brain edema and changes in some pro-inflammatory cytokines was investigated after traumatic brain injury (TBI). MATERIALS AND METHODS: In this study, adult male Wistar rats were divided into 5 groups: Sham, TBI, vehicle (Veh), and low dose (LA) and high dose (HA) Aloe vera. The vehicle and aqueous extract of Aloe vera were injected intraperitoneally 30 min after induction of diffuse TBI by Marmarou's method. Brain edema (brain water content), and transforming growth factor beta (TGF-ß), tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6) and IL-1ß levels in serum and brain were measured 24 hr after TBI induction. RESULTS: Increased brain edema by TBI was reduced by both LA and HA (p<0.01 and p<0.05, respectively). IL-6 increased in the brain of TBI group compared to sham, and which was inhibited by both Aloe vera doses compared to Veh (p<0.001). The differences in the IL-6 serum levels among Veh, LA and HA groups were not significant. Increases in serum and brain IL-1ß levels were reduced only in the HA group (p<0.001). Although only in the brain, TNF-α level increased after trauma, but both LA and HA inhibited it in a dose-dependent manner (p<0.01 and p<0.05, respectively) . The amount of TGF-ß in the brain was reduced by both doses of the extract (p<0.001). CONCLUSION: These results indicated that Aloe vera has a neuroprotective effect induced by reducing brain edema. The probable mechanism particularly for HA is decreasing levels of pro-inflammatory cytokines such as TGF-ß, TNF-α, IL-6 and IL-1ß.
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Glioblastoma multiforme (GBM), as one of the immunosuppressive and common intrinsic brain tumors in adults, remains an intractable malignancy to manage. Since the standard of care for treatment, which includes surgery and chemoradiation, has not provided a sustainable and durable response in affected patients, seeking novel therapeutic approaches to treat GBM seems imperative. Immunotherapy, a breakthrough for cancer treatment, has become an attractive tool for combating cancer with the potential to access the blood-brain-barrier (BBB). In this regard, programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), as major immunological checkpoints, have drawn considerable interest due to their effectiveness in a spectrum of highly-aggressive neoplasms through negative regulation of the T-cell-mediated immune response. Nevertheless, due to the immunosuppressive microenvironment of GBM, the efficacy of these immune checkpoint inhibitors (ICIs), when used as monotherapy, has been unfavorable and lacks sufficient beneficial outcomes for GBM patients. A variety of clinical studies are attempting to evaluate the combination of ICIs (neoadjuvant/adjuvant) and existing treatment guidelines to strengthen their effectiveness; however, the exact mechanism of this signaling axis affects the consequences of immune therapy remains elusive. This review provides an overview of the PD-1/PD-L1 pathway, currently approved ICIs for clinical use, preclinical and clinical trials of PD-1/PD-L1 as monotherapy, and when used concomitantly with other GBM treatments.