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1.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209674

RESUMO

Pre-mRNA processing factor 4B (PRP4) has previously been shown to induce epithelial-mesenchymal transition (EMT) and drug resistance in cancer cell lines. As melanin plays an important photoprotective role in the risk of sun-induced skin cancers, we have investigated whether PRP4 can induce drug resistance and regulate melanin biosynthesis in a murine melanoma (B16F10) cell line. Cells were incubated with a crucial melanogenesis stimulator, alpha-melanocyte-stimulating hormone, followed by transfection with PRP4. This resulted in the inhibition of the production of melanin via the downregulation of adenylyl cyclase-cyclic adenosine 3',5'-monophosphate (AC)-(cAMP)-tyrosinase synthesis signaling pathway. Inhibition of melanin production by PRP4 leads to the promotion of carcinogenesis and induced drug resistance in B16F10 cells. Additionally, PRP4 overexpression upregulated the expression of ß-arrestin 1 and desensitized the extracellular calcium-sensing receptor (CaSR), which in turn, inhibited the influx of extracellular Ca2+ ions. The decreased influx of Ca2+ was confirmed by a decreased expression level of calmodulin. We have demonstrated that transient receptor potential cation channel subfamily C member 1 was involved in the influx of CaSR-induced Ca2+ via a decreasing level of its expression. Furthermore, PRP4 overexpression downregulated the expression of AC, decreased the synthesis of cAMP, and modulated the actin cytoskeleton by inhibiting the expression of Ras homolog family member A (RhoA). Our investigation suggests that PRP4 inhibits the production of melanin in B16F10 cells, blocks the influx of Ca2+ through desensitization of CaSR, and modulates the actin cytoskeleton through downregulating the AC-cAMP pathway; taken together, these observations collectively lead to the promotion of skin carcinogenesis.


Assuntos
Citoesqueleto de Actina/metabolismo , Cálcio/metabolismo , Melaninas/biossíntese , Ribonucleoproteína Nuclear Pequena U4-U6/metabolismo , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/metabolismo , Animais , Antineoplásicos , Calmodulina/genética , Calmodulina/metabolismo , Proteínas de Transporte , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Espaço Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Espaço Intracelular/metabolismo , Melanoma Experimental , Camundongos , Ligação Proteica , Ribonucleoproteína Nuclear Pequena U4-U6/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/patologia
2.
Int J Mol Sci ; 22(12)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34203049

RESUMO

The present study aims to determine the neuroprotective effect of Bergenin against spatial memory deficit associated with neurodegeneration. Preliminarily, the protective effect of Bergenin was observed against H2O2-induced oxidative stress in HT-22 and PC-12 cells. Further studies were performed in 5xFAD Tg mouse model by administering Bergenin (1, 30 and 60 mg/kg; orally), whereas Bergenin (60 mg/kg) significantly attenuated the memory deficit observed in the Y-maze and Morris water maze (MWM) test. Fourier transform-infrared (FT-IR) spectroscopy displayed restoration of lipids, proteins and their derivatives compared to the 5xFAD Tg mice group. The differential scanning calorimeter (DSC) suggested an absence of amyloid beta (Aß) aggregation in Bergenin-treated mice. The immunohistochemistry (IHC) analysis suggested the neuroprotective effect of Bergenin by increasing Reelin signaling (Reelin/Dab-1) and attenuated Aß (1-42) aggregation in hippocampal regions of mouse brains. Furthermore, IHC and western blot results suggested antioxidant (Keap-1/Nrf-2/HO-1), anti-inflammatory (TLR-4/NF-kB) and anti-apoptotic (Bcl-2/Bax/Caspase-3) effect of Bergenin. Moreover, a decrease in Annexin V/PI-stained hippocampal cells suggested its effect against neurodegeneration. The histopathological changes were reversed significantly by Bergenin. In addition, a remarkable increase in antioxidant level with suppression of pro-inflammatory cytokines, oxidative stress and nitric oxide production were observed in specific regions of the mouse brains.


Assuntos
Benzopiranos/farmacologia , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Benzopiranos/química , Biomarcadores , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Ligação de Hidrogênio , Mediadores da Inflamação/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/diagnóstico , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade , Resultado do Tratamento
3.
Viral Immunol ; 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34101517

RESUMO

Coronavirus disease 2019 (COVID-19) is a worldwide emergency that has affected millions of populations in developed and underdeveloped countries. To our surprise, many people have been tested positive twice. Few cases of true reinfections involved genetic alterations in the virus. Appearance of multiple positive tests may be due to human errors or remnant genetic material, but genetic modification in virus represents very serious issue of controlling this pandemic. It is the need of the day that all the gaps and deficiencies, represented by variable response of adaptive immune system toward this infection, be filled and rectified. We have discussed reinfections with variable outcomes along with the possible reasons for variable response. Phenomena such as T cell memory, absence of cross-reactive immunity, T cell exhaustion, drawbacks pertaining to neutralizing antibodies, and immune enhancement are crucial areas by which adaptive immune response can weaken considerably. Earlier and stronger herd immunity is also at the mercy of strong adaptive immune system to avoid future pandemics by the same microorganism. Likewise, consequences of this phenomenon should also be considered during vaccine development as resources worth billions are being used and staked. Many countries have entered the second/third waves of COVID-19. Therefore, we need to come up with ways toward uniform strengthening of adaptive immune response to fight off this pandemic. Also, to develop and maintain constant resistance to severe acute respiratory syndrome coronavirus (SARS-CoV-2), the mentioned weakened links in the chain of adaptive immunity may be explored to keep viral invasion and physiological damage to minimum.

4.
Naunyn Schmiedebergs Arch Pharmacol ; 394(7): 1497-1519, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33713158

RESUMO

In the current study, the N-benzylidene-4-((2-hydroxynaphthalene-1-yl) diazenyl) hydrazides (NCHDH and NTHDH) were evaluated against the Carrageenan- and CFA-induced models. During the preliminary investigation, the NCHDH and NTHDH treatment showed marked anti-inflammatory and analgesic activity against the Carrageenan-induced acute model. Once the anti-inflammatory activity was established against acute Carrageenan model, the NCHDH and NTHDH were evaluated against the chronic CFA-induced arthritis model. The NCHDH and NTHDH treatment markedly attenuated the inflammatory and analgesic parameters compared to CFA-treated group. Furthermore, the increase in the oxidative stress and attenuation of antioxidant enzymes has been reported following CFA administration. However, NCHDH and NTHDH treatment significantly induced the antioxidants and attenuated the oxidative stress markers. The CFA administration showed marked tailing of DNA; however, the NCHDH- and NTHDH-treated group preserved DNA integrity. Furthermore, the histological studies showed marked alteration in the CFA-treated group; however, the NCHDH and NTHDH treatment markedly improved the histological features. The Western blot, immunohistology, and ELISA assay revealed marked increase in the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Jun N-terminal Kinase (JNK), TNF-α, and COX-2 levels; however, the NCHDH and NTHDH attenuated their expressions significantly. Similarly, the NCHDH and NTHDH significantly induced the mRNA expression levels of heat shock proteins. The computational analysis showed significant binding interaction with various protein targets via multiple hydrogens, and hydrophobic bonds. The in vivo pharmacokinetic study was also performed to assess the various pharmacokinetic parameters. In conclusion, the NCHDH and NTHDH treatment showed significant anti-arthritic activity against Carrageenan and CFA models.

5.
Pharmacol Ther ; 223: 107806, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33465400

RESUMO

Cancer promotion, development, and malignant transformation is greatly influenced by cell-to-cell interactions in a complex tissue microenvironment. Cancer and stromal cells secrete soluble factors, as well as deport membrane-encapsulated structures, which actively contribute and mediate cell-to-cell interaction within a tumor microenvironment (TME). These membrane structures are recognized as extracellular vesicles (EVs), which include exosomes and microvesicles. They can carry and transport regulatory molecules such as oncogenic proteins, coding and non-coding RNAs, DNA, and lipids between neighboring cells and to distant sites. EVs mediate crucial pathophysiological effects such as the formation of premetastatic niches and the progression of malignancies. There is compelling evidence that cancer cells exhibit a significant amount of EVs, which can be released into the surrounding body fluids, compared with nonmalignant cells. EVs therefore have the potential to be used as disease indicator for the diagnosis and prognosis of cancers, as well as for facilitating research into the underlying mechanism and biomolecular basis of these diseases. Because of their ability to transport substances, followed by their distinct immunogenicity and biocompatibility, EVs have been used to carry therapeutically-active molecules such as RNAs, proteins, short and long peptides, and various forms of drugs. In this paper, we summarize new advancement in the biogenesis and physiological roles of EVs, and underpin their functional impacts in the process of cancer growth and metastasis. We further highlight the therapeutic roles of EVs in the treatment, prevention, and diagnosis of human malignancies.

6.
Int J Biol Macromol ; 168: 301-309, 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33316340

RESUMO

Bacterial cellulose (BC) has received immense interest in medical, pharmaceutical, and other related fields owing to its intrinsic physical, mechanical, and biological features. Its structural features offer an ideal environment for developing composites, thereby further extending its areas of applications. BC was initially used in wound dressing, artificial blood vessels, organ development, and tissue regeneration; however, the recent focus has switched to 3D printing techniques. BC can serve as suitable material for treating different cancers due to unique liquid absorbing and drug loading properties. BC-based scaffolds have been synthesized and tested for in vitro culturing of cancer cells to simulate tumor microenvironments. These scaffolds support normal growth of cancer cells, particularly breast and ovarian cancer cells, showing significant adhesion, proliferation, ingrowth, and differentiation. This review describes the different approaches of manipulating BC for use in medicine, with particular focus on the applications of BC composites in cancer treatment. A detailed discussion about various formulations of BC in multiple cancer therapeutics is summarized.


Assuntos
Celulose/química , Celulose/farmacologia , Neoplasias/tratamento farmacológico , Bactérias/química , Proteínas de Bactérias/farmacologia , Materiais Biocompatíveis/química , Engenharia Tecidual/métodos , Tecidos Suporte/química , Cicatrização/fisiologia
7.
Curr Pharm Des ; 26(45): 5783-5792, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33213321

RESUMO

There is compelling evidence that drug molecules isolated from natural sources are hindered by low systemic bioavailability, poor absorption, and rapid elimination from the human body. Novel approaches are urgently needed that could enhance the retention time as well as the efficacy of natural products in the body. Among the various adopted approaches to meet this ever-increasing demand, nanoformulations show the most fascinating way of improving the bioavailability of dietary phytochemicals through modifying their pharmacokinetics and pharmacodynamics. Curcumin, a yellowish pigment isolated from dried ground rhizomes of turmeric, exhibits tremendous pharmacological effects, including anticancer activities. Several in vitro and in vivo studies have shown that curcumin mediates anticancer effects through the modulation (upregulation and/or downregulations) of several intracellular signaling pathways both at protein and mRNA levels. Scientists have introduced multiple modern techniques and novel dosage forms for enhancing the delivery, bioavailability, and efficacy of curcumin in the treatment of various malignancies. These novel dosage forms include nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles. Nanocurcumin has shown improved anticancer effects compared to conventional curcumin formulations. This review discusses the underlying molecular mechanism of various nanoformulations of curcumin for the treatment of different cancers. We hope that this study will make a road map for preclinical and clinical investigations of cancer and recommend nano curcumin as a drug of choice for cancer therapy.


Assuntos
Curcumina , Nanopartículas , Neoplasias , Disponibilidade Biológica , Curcumina/farmacologia , Humanos , Micelas , Neoplasias/tratamento farmacológico
8.
Curr Pharm Des ; 26(45): 5767-5782, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32988346

RESUMO

BACKGROUND: Conventional practices of synthesis, manufacturing, and processing have led to severe adverse consequences for living beings and the environment. OBJECTIVES: Although medications cannot be replaced, the methods of synthesizing, manufacturing, and processing them can be changed and/or replaced. This paper explains the significance of green chemistry practices in the pharmaceutical industry. It emphasizes that we must replace conventional drug synthesis, processing, and manufacturing techniques with greener ones that are cost-effective, sustainable, environment-friendly, and profitable. DISCUSSION: This paper comprises five sections. Section 1 is an introduction to green chemistry and its correlation with the pharmaceutical industry. Section 2 discusses the metrics necessary to measure the greenness of a process. Section 3 is about solvents used in the pharmaceutical industry, hazards, safety status, and environmental effects, including the ozone depletion potential. Section 4 explains catalytic amidation reactions because amides are one of the most commonly occurring functional groups with pharmacological activity. Section 5 discusses successful cases of converting conventional synthesis of active pharmaceutical ingredients and/or their intermediates to greener, sustainable alternatives. CONCLUSION: A balance is necessary between profits, processes, consumers, and the environment to ensure the survival of all stakeholders and decrease the environmental burden of pharmaceuticals. Incentives such as green chemistry awards should be endorsed and encouraged, in addition to making green chemistry part of tertiary education. In addition, changes to rules and regulations for drug approval in the context of green chemistry principles are necessary in order to preserve our planet for future generations.


Assuntos
Indústria Farmacêutica , Preparações Farmacêuticas , Comércio , Humanos , Solventes
9.
Antioxidants (Basel) ; 9(10)2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32993035

RESUMO

Human skin is continuously subjected to environmental stresses, as well as extrinsic and intrinsic noxious agents. Although skin adopts various molecular mechanisms to maintain homeostasis, excessive and repeated stresses can overwhelm these systems, leading to serious cutaneous damage, including both melanoma and non-melanoma skin cancers. Phytochemicals present in the diet possess the desirable effects of protecting the skin from damaging free radicals as well as other benefits. Dietary phytochemicals appear to be effective in preventing skin cancer and are inexpensive, widely available, and well tolerated. Multiple in vitro and in vivo studies have demonstrated the significant anti-inflammatory, antioxidant, and anti-angiogenic characteristics of dietary phytochemicals against skin malignancy. Moreover, dietary phytochemicals affect multiple important cellular processes including cell cycle, angiogenesis, and metastasis to control skin cancer progression. Herein, we discuss the advantages of key dietary phytochemicals in whole fruits and vegetables, their bioavailability, and underlying molecular mechanisms for preventing skin cancer. Current challenges and future prospects for research are also reviewed. To date, most of the chemoprevention investigations have been conducted preclinically, and additional clinical trials are required to conform and validate the preclinical results in humans.

10.
Mol Cells ; 43(7): 662-670, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32576716

RESUMO

We have investigated the involvement of the pre-mRNA processing factor 4B (PRP4) kinase domain in mediating drug resistance. HCT116 cells were treated with curcumin, and apoptosis was assessed based on flow cytometry and the generation of reactive oxygen species (ROS). Cells were then transfected with PRP4 or pre-mRNA-processing-splicing factor 8 (PRP8), and drug resistance was analyzed both in vitro and in vivo. Furthermore, we deleted the kinase domain in PRP4 using GatewayTM technology. Curcumin induced cell death through the production of ROS and decreased the activation of survival signals, but PRP4 overexpression reversed the curcumin-induced oxidative stress and apoptosis. PRP8 failed to reverse the curcumin-induced apoptosis in the HCT116 colon cancer cell line. In xenograft mouse model experiments, curcumin effectively reduced tumour size whereas PRP4 conferred resistance to curcumin, which was evident from increasing tumour size, while PRP8 failed to regulate the curcumin action. PRP4 overexpression altered the morphology, rearranged the actin cytoskeleton, triggered epithelial-mesenchymal transition (EMT), and decreased the invasiveness of HCT116 cells. The loss of E-cadherin, a hallmark of EMT, was observed in HCT116 cells overexpressing PRP4. Moreover, we observed that the EMT-inducing potential of PRP4 was aborted after the deletion of its kinase domain. Collectively, our investigations suggest that the PRP4 kinase domain is responsible for promoting drug resistance to curcumin by inducing EMT. Further evaluation of PRP4-induced inhibition of cell death and PRP4 kinase domain interactions with various other proteins might lead to the development of novel approaches for overcoming drug resistance in patients with colon cancer.


Assuntos
Apoptose/genética , Neoplasias Colorretais/metabolismo , Curcumina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Proteínas Serina-Treonina Quinases/metabolismo , Ribonucleoproteína Nuclear Pequena U4-U6/metabolismo , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caderinas/genética , Caderinas/metabolismo , Domínio Catalítico , Neoplasias Colorretais/genética , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Ribonucleoproteína Nuclear Pequena U4-U6/genética , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Molecules ; 25(8)2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32326318

RESUMO

Although the global prevalence of neurological disorders such as Parkinson's disease, Alzheimer's disease, glioblastoma, epilepsy, and multiple sclerosis is steadily increasing, effective delivery of drug molecules in therapeutic quantities to the central nervous system (CNS) is still lacking. The blood brain barrier (BBB) is the major obstacle for the entry of drugs into the brain, as it comprises a tight layer of endothelial cells surrounded by astrocyte foot processes that limit drugs' entry. In recent times, intranasal drug delivery has emerged as a reliable method to bypass the BBB and treat neurological diseases. The intranasal route for drug delivery to the brain with both solution and particulate formulations has been demonstrated repeatedly in preclinical models, including in human trials. The key features determining the efficacy of drug delivery via the intranasal route include delivery to the olfactory area of the nares, a longer retention time at the nasal mucosal surface, enhanced penetration of the drugs through the nasal epithelia, and reduced drug metabolism in the nasal cavity. This review describes important neurological disorders, challenges in drug delivery to the disordered CNS, and new nasal delivery techniques designed to overcome these challenges and facilitate more efficient and targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices.


Assuntos
Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Nanomedicina Teranóstica , Administração Intranasal , Animais , Barreira Hematoencefálica/metabolismo , Doenças do Sistema Nervoso Central/tratamento farmacológico , Vias de Administração de Medicamentos , Portadores de Fármacos , Humanos , Nanopartículas/química , Permeabilidade
12.
Anim Cells Syst (Seoul) ; 24(1): 44-52, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32158615

RESUMO

The current investigation was carried out to analyze the correlation of bacterial lipopolysaccharide (LPS) and pre-mRNA processing factor 4B (PRP4) in inducing inflammatory response and cell actin cytoskeleton rearrangement in macrophages (Raw 264.7) and colorectal (HCT116) as well as skin cancer (B16-F10) cells. Cell lines were stimulated with LPS, and the expression of PRP4 as well as pro-inflammatory cytokines and proteins like IL-6, IL-1ß, TLR4, and NF-κB were assayed. The results demonstrated that LPS markedly increased the expression of PRP4, IL-6, IL-1ß, TLR4, and NF-κB in the cells. LPS and PRP4 concomitantly altered the morphology of cells from an aggregated, flattened shape to a round shape. Decursin, a pyranocoumarin from Angelica gigas, inhibited the LPS and PRP4-induced inflammatory response, and reversed the induction of morphological changes. Finally, we established a possible link of LPS with TLR4 and JNK signaling, through which it activated PRP4. Our study provides molecular insights for LPS and PRP4-related pathogenesis and a basis for developing new strategies against metastasis in colorectal cancer and skin melanoma. Our study emphasizes that decursin may be an effective treatment strategy for various cancers in which LPS and PRP4 perform a critical role in inducing inflammatory response and morphological changes leading to cell survival and protection against anti-cancer drugs.

13.
Int Immunopharmacol ; 80: 106209, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32004924

RESUMO

The present study investigated the effect of the continentalic acid (CNT) isolated from the Aralia Continentalis against the LPS and E. coli-induced nephrotoxicity. The LPS and E. coli administration markedly altered the behavioral parameters including spontaneous pain, tail suspension and survival rate. However, the treatment with CNT dose dependently improved the behavioral parameters. The CNT treatment significantly improved the renal functions test (RFTs) and hematological parameters following LPS and E. coli-induced kidney injury. Furthermore, the LPS and E. coli administration markedly compromised the anti-oxidant enzymes and enhanced the oxidative stress markers. However, the CNT treatment markedly enhanced the anti-oxidants enzymes such as GSH, GST, Catalase and SOD, while attenuated the oxidative stress markers such as MDA and POD. The MPO enzyme is widely used marker for the neutrophilic infiltration, the LPS and E. coli administration markedly increased the MPO activity. However, the CNT treatment markedly attenuated the MPO activity in both LPS and E. coli-induced kidney injury. Furthermore, the CNT treatment markedly attenuated the NO production compared to the LPS and E. coli-induced kidney injury group. Additionally, the CNT treatment improved the histological parameters markedly (H and E, PAS and Masson's trichome staining) and protect the kidney from the inflammatory insult of the LPS and E. coli evidently. The comet assay revealed marked DNA damage, however, the CNT treatment markedly prevented the LPS and E. coli-induced kidney damage. The CNT treatment markedly enhanced the expression of Nrf2, while attenuated the iNOS expression in both models of kidney injury.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Diterpenos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/patologia , Animais , Aralia/química , Modelos Animais de Doenças , Diterpenos/uso terapêutico , Escherichia coli/imunologia , Humanos , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Lipopolissacarídeos/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/imunologia , Substâncias Protetoras/uso terapêutico
14.
Life Sci ; 239: 116888, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31639401

RESUMO

5-Fluorouracil (5-FU)-induced intestinal mucositis (IM) is one of the most common oncological problem. It involves serious clinical consequences such as diarrhea, erythematous lesions of mucosa, and eventually development of ulcers accompanied by severe pain. The aim of the present study was to demonstrate the mucoprotective effects of Saikosaponin-A in 5-FU-induced intestinal mucositis in mice. Mucositis was induced in BALB/c mice by intraperitoneal injection of 5-FU (50 mg/kg/day) for three consecutive days and IM was assessed by both behavioral and histochemical analysis. While, Saikosaponin-A (1, 5, 10 mg/kg/day) was administered 1 h before 5-FU injection for consecutive seven days. Pre-treatment of Saikosaponin-A significantly ameliorated the severity of mucositis reflected as food intake, body weight loss, severity of diarrhea and mortality rate in a dose depended manner as compared to mice treated with 5-FU. Moreover, histopathological analysis furthered reinforced the mucoprotective potential of Saikosaponin-A against 5-FU-induced intestinal abnormalities referred as villus atrophy, mitotic crypt stem cells damage, inflammatory cells infiltration, vacuolization and edema. Furthermore, Saikosaponin-A administration strongly inhibited pro-inflammatory mediators (TNF-α, COX-2, IL-1ß and IL-6) and apoptotic markers (p-JNK, Casp-3). Saikosaponin-A pre-treatment significantly reduced the production of nitric oxide (NO) in intestinal tissue, inhibited acetic acid-induced Evans blue vascular permeability. The Siaikosaponin-A treatment markedly enhanced the anti-oxidants enzymes (Nrf2, HO-1, SOD, GSH, GST and Catalase), while decreased the oxidative stress markers i.e. Malonaldehde (MDA). Hence, these data suggest that Saikosaponin-A maybe a potential candidate for the treatment of chemotherapy-induced intestinal mucositis.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , Mucosite/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Citocinas , Diarreia/induzido quimicamente , Modelos Animais de Doenças , Fluoruracila/farmacologia , Mucosa Intestinal/patologia , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mucosite/metabolismo , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , Saponinas/metabolismo
15.
Int J Biol Macromol ; 137: 1050-1059, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31295500

RESUMO

Bacterial cellulose (BC) has emerged as a biomaterial for diverse biomedical applications owing to its unique structural, physico-chemical, mechanical, and biological features. Its porous geometry and three-dimensional fibrous structure allow the impregnation of various materials into its matrix. The current study was aimed to fabricate 3D scaffolds of bacterial cellulose and chitosan (BC-Chi) through a one-step ex situ solution impregnation strategy and analyze the scaffold interaction with the ovarian cancer cell lines (A2780). Field emission scanning electron microscopy (FE-SEM) showed successful impregnation of chitosan into the BC matrix. Phase-contrast and confocal microscopy analyses revealed that human ovarian cancer cell lines (A2780) were adhered not only to the surface but deeply infiltrated into the matrix of BC-Chi scaffold. WST-1 assay, histology analysis, and cytoskeleton and nuclear staining showed high viability, proliferation, and infiltration of A2780 cell lines into the scaffold. The RT-PCR analysis revealed a decreased mRNA level of Notch receptors, indicating a strong cell-scaffold interaction. The improved biocompatibility, non-toxicity, and 3D structure of fabricated BC-Chi scaffold justify its potential applications diagnosis of ovarian cancer in vivo.


Assuntos
Comunicação Celular/efeitos dos fármacos , Celulose/química , Quitosana/química , Quitosana/farmacologia , Gluconacetobacter xylinus/química , Neoplasias Ovarianas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Fenômenos Mecânicos , Receptores Notch/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-31198432

RESUMO

Artemia salina, crustaceans of class Branchiopoda and order Anostraca, are living and reproducing only in highly saline natural lakes and in other reservoirs where sea water is evaporated to produce salt. Artemia salina eggs can be purchased from pet stores, where they are sold as tropical fish food and a ready source for hatching shrimp. In the current study, methanolic crude extracts and various fractions of Artemia salina eggs extracted in other solvents were tested for effects on cell viability of human colorectal cancer cells (HCT116) and melanoma cells (B16F10) using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. A methanolic crude extract of eggs was obtained by cold maceration, followed by fractionation to obtain hexane, chloroform, ethyl acetate, n-butanol, and aqueous fractions. The methanolic crude extract decreased cell viability of HCT-116 and B16F10 cell lines at higher concentrations. The other fractions were evaluated using a cell viability assay, and chloroform and hexane showed the highest activity at significantly lower concentrations than did the methanolic fraction. Full scan profiles of the methanolic crude extract and the chloroform and hexane fractions were obtained by gas chromatography mass spectrometry (GC-MS), and the resultant compounds were identified by comparing their spectral data to those available in spectral matching libraries. ROS generation assay, flow cytometry, and western blot analysis provided supporting evidence that the hexane and chloroform fractions induced cell death in HCT116 and B16-F10 cell lines. All fractions were further tested for antibacterial activity against Pseudomonas aeruginosa, among which the hexane fraction showed the highest zone of inhibition on LB nutrient agar plates. This study demonstrated promising anticancer and antibacterial effects of Artemia salina egg extracts. Our results suggest that pure bioactive compounds obtained from Artemia salina eggs can provide new insights into the mechanisms of colon and skin cancer, as well as Pseudomonas aeruginosa inhibition.

17.
Molecules ; 23(8)2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-30060484

RESUMO

Inflammation is considered the root cause of various inflammatory diseases, including cancers. Decursinol angelate (DA), a pyranocoumarin compound obtained from the roots of Angelica gigas, has been reported to exhibit potent anti-inflammatory effects. In this study, the anti-inflammatory effects of DA on the MAP kinase and NFκB signaling pathways and the expression of pro-inflammatory cytokines were investigated in phorbol 12-myristate 13-acetate (PMA)-activated human promyelocytic leukemia (HL-60) and lipopolysaccharide (LPS)-stimulated macrophage (Raw 264.7) cell lines. PMA induced the activation of the MAP kinase-NFκB pathway and the production of pro-inflammatory cytokines in differentiated monocytes. Treatment with DA inhibited the activation of MAP kinases and the translocation of NFκB, and decreased the expression and exogenous secretion of IL-1ß and IL-6. Furthermore, LPS-stimulated Raw 264.7 cells were found to have increased expression of M1 macrophage-associated markers, such as NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS), and the M2 macrophage-associated marker CD11b. LPS also activated pro-inflammatory cytokines and Erk-NFκB. Treatment with DA suppressed LPS-induced macrophage polarization and the inflammatory response by blocking Raf-ERK and the translocation of NFκB in Raw 264.7 cells. Treatment with DA also inhibited the expression of pro-inflammatory cytokines, such as IL-1ß and IL-6, NOX, and iNOS in Raw 264.7 cells. These results suggest that DA has the potential to inhibit macrophage polarization and inflammation by blocking the activation of pro-inflammatory signals. These anti-inflammatory effects of DA may contribute to its potential use as a therapeutic strategy against various inflammation-induced cancers.


Assuntos
Anti-Inflamatórios/farmacologia , Benzopiranos/farmacologia , Butiratos/farmacologia , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/citologia , NF-kappa B/metabolismo , Animais , Polaridade Celular/efeitos dos fármacos , Citocinas/metabolismo , Células HL-60 , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Ésteres de Forbol/farmacologia , Transporte Proteico/efeitos dos fármacos , Células RAW 264.7
18.
Int J Biol Macromol ; 117: 1200-1210, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29894790

RESUMO

This study reports the fabrication of porogen-induced, surface-modified, 3-dimensionally microporous regenerated bacterial cellulose (rBC)/gelatin (3DMP rBC/G) scaffolds for skin regeneration applications. Round shaped gelatin microspheres (GMS), fabricated using a water-in-oil emulsion (WOE) method, were utilized as the porogen. The dissolution of GMS from the solution casted BC scaffolds led to surface-modified microporous rBC. The scaffolds were characterized using field emission scanning electron microscopy (FE-SEM) and elemental analysis. FE-SEM analysis confirmed the regular microporosity of the 3DMP rBC/G scaffolds, while elemental analysis confirmed the successful surface modification of cellulose with gelatin. In vitro tests showed good adhesion and proliferation of human keratinocytes (HaCaT) on the 3DMP rBC/G scaffolds during 7 days of incubation. Confocal microscopy showed penetration of HaCaT cells into the scaffolds, up to 300 µm in depth. In vivo wound healing and skin regeneration experiments, in experimental mice, showed complete skin regeneration within 2 weeks. The wound closure efficacy of the 3DMP rBC/G scaffolds was much higher (93%) than that of the control (47%) and pure BC-treated (63%) wounds. These results indicated that our 3DMP rBC/G scaffolds represent future candidate materials for skin regeneration applications.


Assuntos
Bactérias/química , Materiais Biocompatíveis/química , Celulose/química , Celulose/isolamento & purificação , Microesferas , Tecidos Suporte/química , Adesão Celular , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular , Humanos , Queratinócitos , Teste de Materiais , Porosidade , Impressão Tridimensional , Regeneração , Pele/citologia , Fenômenos Fisiológicos da Pele , Engenharia Tecidual , Cicatrização
19.
Exp Cell Res ; 369(1): 158-165, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29787735

RESUMO

Cell actin cytoskeleton is primarily modulated by Rho family proteins. RhoA regulates several downstream targets, including Rho-associated protein kinase (ROCK), LIM-Kinase (LIMK), and cofilin. Pre-mRNA processing factor 4B (PRP4) modulates the actin cytoskeleton of cancer cells via RhoA activity inhibition. In this study, we discovered that PRP4 over-expression in HCT116 colon cancer cells induces cofilin dephosphorylation by inhibiting the Rho-ROCK-LIMK-cofilin pathway. Two-dimensional gel electrophoresis, and matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry (MALDI-TOF MS) analysis indicated increased expression of protein phosphatase 1A (PP1A) in PRP4-transfected HCT116 cells. The presence of PRP4 increased the expression of PP1A both at the mRNA and protein levels, which possibly activated cofilin through dephosphorylation and subsequently modulated the cell actin cytoskeleton. Furthermore, we found that PRP4 over-expression did not induce cofilin dephosphorylation in the presence of okadaic acid, a potent phosphatase inhibitor. Moreover, we discovered that PRP4 over-expression in HCT116 cells induced dephosphorylation of migration and invasion inhibitory protein (MIIP), and down-regulation of E-cadherin protein levels, which were further restored by the presence of okadaic acid. These findings indicate a possible molecular mechanism of PRP4-induced actin cytoskeleton remodeling and epithelial-mesenchymal transition, and make PRP4 an important target in colon cancer.


Assuntos
Citoesqueleto de Actina/metabolismo , Fatores de Despolimerização de Actina/metabolismo , Actinas/metabolismo , Transição Epitelial-Mesenquimal/genética , Proteínas Serina-Treonina Quinases/fisiologia , Ribonucleoproteína Nuclear Pequena U4-U6/fisiologia , Citoesqueleto de Actina/genética , Adesão Celular/genética , Movimento Celular/genética , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Citoesqueleto/genética , Citoesqueleto/metabolismo , Células HCT116 , Humanos , Quinases Lim/metabolismo , Invasividade Neoplásica , Proteínas Serina-Treonina Quinases/metabolismo , Ribonucleoproteína Nuclear Pequena U4-U6/metabolismo , Transdução de Sinais , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
20.
Oncotarget ; 8(34): 56659-56671, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28915620

RESUMO

Pre-mRNA processing factor (PRPF) 4B kinase belongs to the CDK-like kinase family, and is involved in pre-mRNA splicing, and in signal transduction. In this study, we observed that PRPF overexpression decreased the intracellular levels of reactive oxygen species, and inhibited resveratrol-induced apoptosis by activating the cell survival signaling proteins NFκB, ERK, and c-MYC in HCT116 human colon cancer cells. PRPF overexpression altered cellular morphology, and rearranged the actin cytoskeleton, by regulating the activity of Rho family proteins. Moreover, it decreased the activity of RhoA, but increased the expression of Rac1. In addition, PRPF triggered the epithelial-mesenchymal transition (EMT), and decreased the invasiveness of HCT116, PC3 human prostate, and B16-F10 melanoma cells. The loss of E-cadherin, a hallmark of EMT, was observed in HCT116 cells overexpressing PRPF. Taken together, these results indicate that PRPF blocks the apoptotic effects of resveratrol by activating cell survival signaling pathways, rearranging the actin cytoskeleton, and inducing EMT. The elucidation of the mechanisms that underlie anticancer drug resistance and the anti-apoptosis effect of PRPF may provide a therapeutic basis for inhibiting tumor growth and preventing metastasis in various cancers.

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