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1.
Environ Res ; 244: 117949, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38109961

RESUMO

Petrochemical-based synthetic plastics poses a threat to humans, wildlife, marine life and the environment. Given the magnitude of eventual depletion of petrochemical sources and global environmental pollution caused by the manufacturing of synthetic plastics such as polyethylene (PET) and polypropylene (PP), it is essential to develop and adopt biopolymers as an environment friendly and cost-effective alternative to synthetic plastics. Research into bioplastics has been gaining traction as a way to create a more sustainable and eco-friendlier environment with a reduced environmental impact. Biodegradable bioplastics can have the same characteristics as traditional plastics while also offering additional benefits due to their low carbon footprint. Therefore, using organic waste from biological origin for bioplastic production not only reduces our reliance on edible feedstock but can also effectively assist with solid waste management. This review aims at providing an in-depth overview on recent developments in bioplastic-producing microorganisms, production procedures from various organic wastes using either pure or mixed microbial cultures (MMCs), microalgae, and chemical extraction methods. Low production yield and production costs are still the major bottlenecks to their deployment at industrial and commercial scale. However, their production and commercialization pose a significant challenge despite such potential. The major constraints are their production in small quantity, poor mechanical strength, lack of facilities and costly feed for industrial-scale production. This review further explores several methods for producing bioplastics with the aim of encouraging researchers and investors to explore ways to utilize these renewable resources in order to commercialize degradable bioplastics. Challenges, future prospects and Life cycle assessment of bioplastics are also highlighted. Utilizing a variety of bioplastics obtained from renewable and cost-effective sources (e.g., organic waste, agro-industrial waste, or microalgae) and determining the pertinent end-of-life option (e.g., composting or anaerobic digestion) may lead towards the right direction that assures the sustainable production of bioplastics.


Assuntos
Compostagem , Plásticos , Humanos , Biopolímeros/química , Tecnologia , Resíduos Industriais
2.
Health Info Libr J ; 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39046201

RESUMO

The study is a part of a student research project on performance-based evaluation of big data application in health sciences libraries. It presents a theoretical framework of the performance-based evaluation system for health institutes' libraries in the digital environment. The health sciences libraries' systematic approach was judged based on the five main components (data culture, organisational infrastructure, responsibilities, skills and technology competence) of big data analytics (BDA). A comprehensive literature review of the published studies was undertaken related to BDA, including the diffusion of innovation theory, and the theoretical background of the technology acceptance model to produce an application-based big data development framework for the health sciences libraries. The application-based evaluation model integrates BDA in health sciences libraries for improving library services and performance. The study proposed a need for skilled professionals with the knowledge and experience both professionally and technically. Finally, the study proposed a model that will help to measure the organisation's ability to analyse vast amounts of data to empirically validate the association concerning big data analysis and analytical practices in health libraries.

3.
Arch Virol ; 168(12): 297, 2023 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-38007412

RESUMO

Lumpy skin disease (LSD) is a contagious viral transboundary disease listed as a notifiable disease by the World Organization of Animal Health (WOAH). The first case of this disease was reported in Pakistan in late 2021. Since then, numerous outbreaks have been documented in various regions and provinces across the country. The current study primarily aimed to analyze samples collected during LSD outbreaks in cattle populations in the Sindh and Punjab provinces of Pakistan. Phylogenetic analysis was conducted using partial sequences of the GPCR, p32, and RP030 genes. Collectively, the LSDV strains originating from outbreaks in Pakistan exhibited a noticeable clustering pattern with LSDV strains reported in African, Middle Eastern, and Asian countries, including Egypt, the Kingdom of Saudi Arabia, India, China, and Thailand. The precise reasons behind the origin of the virus strain and its subsequent spread to Pakistan remain unknown. This underscores the need for further investigations into outbreaks across the country. The findings of the current study can contribute to the establishment of effective disease control strategies, including the implementation of a mass vaccination campaign in disease-endemic countries such as Pakistan.


Assuntos
Doença Nodular Cutânea , Vírus da Doença Nodular Cutânea , Animais , Bovinos , Surtos de Doenças/veterinária , Doença Nodular Cutânea/epidemiologia , Vírus da Doença Nodular Cutânea/genética , Paquistão/epidemiologia , Filogenia
4.
Int J Mol Sci ; 24(24)2023 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-38139116

RESUMO

Ginseng is usually consumed as a daily food supplement to improve health and has been shown to benefit skeletal muscle, improve glucose metabolism, and ameliorate muscle-wasting conditions, cardiovascular diseases, stroke, and the effects of aging and cancers. Ginseng has also been reported to help maintain bone strength and liver (digestion, metabolism, detoxification, and protein synthesis) and kidney functions. In addition, ginseng is often used to treat age-associated neurodegenerative disorders, and ginseng and ginseng-derived natural products are popular natural remedies for diseases such as diabetes, obesity, oxidative stress, and inflammation, as well as fungal, bacterial, and viral infections. Ginseng is a well-known herbal medication, known to alleviate the actions of several cytokines. The article concludes with future directions and significant application of ginseng compounds for researchers in understanding the promising role of ginseng in the treatment of several diseases. Overall, this study was undertaken to highlight the broad-spectrum therapeutic applications of ginseng compounds for health management.


Assuntos
Diabetes Mellitus , Doenças Neurodegenerativas , Panax , Humanos , Obesidade , Inflamação/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico
5.
Molecules ; 28(18)2023 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-37764305

RESUMO

The source and type of collagen are crucial to its application, and both play a decisive role. Collagen was prepared from both tilapia skin and bone and skate skin and cartilage, named as CI-TI-s, CI-TI-b, CI-SK-s, and CII-SK-c, respectively. Types, distributions, structures, and self-assembly of collagen were studied. It showed that yellow collagen fibers from skin arranged longitudinally, while collagen fibers from skate cartilages displayed varying colors. CI-TI-s, CI-TI-b, CI-SK-s, and CII-SK-c showed the typical amide A (3316-3336 cm-1) and amide B (2929-2948 cm-1) in FTIR spectra. CI-TI-b and CII-SK-c showed 218-229 nm of UV absorption, 11.56-12.20 Å of d values in XRD, and 0.12-0.14 of Rpn values in CD. The thermal denaturation temperatures of CI-TI-s and CI-SK-s were 30.7 and 20.6 °C, respectively. The self-assembly of CI-TI-s and CII-SK-c were maximum at pH 7.2 and 7.4-7.6, respectively. The unique collagen peptides of tilapia and skate were GPSGPQGAVGATGPK, PAMPVPGPMGPMGPR, SPAMPVPGPMGPMGPR, GESGPSGPAGPAGPAGVR, SSGPPVPGPIGPMGPR, GLTGPIGVPGPPGAQGEK, GLAGPQGPR, and GLSGDPGVQGIK, respectively. The unique peptides of type I and type II collagen were GPTGEIGATGLAGAR, GVLGLTGMR, LGLTGMR, GEPGAAGPAGPSGPMGPR, SSGPPVPGPIGPMGPR, and GLSGDPGVQGIK, respectively.


Assuntos
Colágeno , Tilápia , Animais , Colágeno/química , Colágeno Tipo II , Pele/química
6.
Semin Cancer Biol ; 69: 325-336, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-31454671

RESUMO

Integrins are the main cell surface receptors and execute multifaceted functions such as the bidirectional transmission of signals (i.e., inside-out and outside-in) and provide communication between cells and their microenvironments. Integrins are the key regulators of critical biological functions and contribute significantly to the promotion of cancer at almost every stage of disease progression from initial tumor formation to metastasis. Integrin expressions are frequently altered in different cancers, and consequently, several therapeutic strategies targeting integrins have been developed. Furthermore, nanotechnology-based approaches have been devised to overcome the intrinsic limitations of conventional therapies for cancer management, and have been shown to more precise, safer, and highly effective therapeutic tools. Although nanotechnology-based approaches have achieved substantial success for the management of cancer, certain obstacles remain such as inadequate knowledge of nano-bio interactions and the challenges associated with the three stages of clinical trials. This review highlights the different roles of integrins and of integrin-dependent signaling in various cancers and describes the applications of nanotherapeutics targeting integrins. In addition, we discuss RGD-based approaches and challenges posed to cancer management.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Integrinas/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Gerenciamento Clínico , Humanos , Nanopartículas/química , Neoplasias/patologia
7.
Langmuir ; 38(20): 6273-6280, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35549237

RESUMO

Molecular dynamics simulations were performed to study nanoscale friction on hydrophilic and hydrophobic self-assembled monolayers (SAMs) immersed in water. Sliding was simulated in two different directions to capture anisotropy due to the direction of motion relative to the inherent tilted orientation of the molecules. It was shown that friction depends on both hydrophobicity and sliding direction, with the highest friction observed for sliding on hydrophobic SAM in the direction against the initial orientation of the molecules. The origins of the friction trends were analyzed by differentiating the tip-SAM and tip-water force contributions to friction. The tip-water force was higher on the hydrophilic SAM, and this was shown to be due to the presence of a dense layer of water adjacent to the surface and hydrogen bonding. In contrast, the tip-SAM force was higher on the hydrophobic SAM due to a water depletion layer, which enabled the tip to be closer to the SAM terminal group. The higher-friction cases all exhibited greater penetration of the tip below the surface of the SAM, accommodated by further tilting and reorientation of the SAM molecules.

8.
Int J Mol Sci ; 23(8)2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35457038

RESUMO

The use of peptides as drugs has progressed over time and continues to evolve as treatment paradigms change and new drugs are developed. Myostatin (MSTN) inhibition therapy has shown great promise for the treatment of muscle wasting diseases. Here, we report the MSTN-derived novel peptides MIF1 (10-mer) and MIF2 (10-mer) not only enhance myogenesis by inhibiting MSTN and inducing myogenic-related markers but also reduce adipogenic proliferation and differentiation by suppressing the expression of adipogenic markers. MIF1 and MIF2 were designed based on in silico interaction studies between MSTN and its receptor, activin type IIB receptor (ACVRIIB), and fibromodulin (FMOD). Of the different modifications of MIF1 and MIF2 examined, Ac-MIF1 and Ac-MIF2-NH2 significantly enhanced cell proliferation and differentiation as compared with non-modified peptides. Mice pretreated with Ac-MIF1 or Ac-MIF2-NH2 prior to cardiotoxin-induced muscle injury showed more muscle regeneration than non-pretreated controls, which was attributed to the induction of myogenic genes and reduced MSTN expression. These findings imply that Ac-MIF1 and Ac-MIF2-NH2 might be valuable therapeutic agents for the treatment of muscle-related diseases.


Assuntos
Doenças Musculares , Miostatina , Animais , Fibromodulina/metabolismo , Camundongos , Desenvolvimento Muscular , Músculo Esquelético/metabolismo , Músculos/metabolismo , Atrofia Muscular/metabolismo , Doenças Musculares/metabolismo , Miostatina/genética , Miostatina/metabolismo , Peptídeos/metabolismo
9.
Molecules ; 27(13)2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35807547

RESUMO

Myostatin (MSTN), a negative regulator of muscle mass, is reported to be increased in conditions linked with muscle atrophy, sarcopenia, and other muscle-related diseases. Most pharmacologic approaches that treat muscle disorders are ineffective, emphasizing the emergence of MSTN inhibition. In this study, we used computational screening to uncover natural small bioactive inhibitors from the Traditional Chinese Medicine database (~38,000 compounds) for the MSTN protein. Potential ligands were screened, based on binding affinity (150), physicochemical (53) and ADMET properties (17). We found two hits (ZINC85592908 and ZINC85511481) with high binding affinity and specificity, and their binding patterns with MSTN protein. In addition, molecular dynamic simulations were run on each complex to better understand the interaction mechanism of MSTN with the control (curcumin) and the hit compounds (ZINC85592908 and ZINC85511481). We determined that the hits bind to the active pocket site (Helix region) and trigger conformational changes in the MSTN protein. Since the stability of the ZINC85592908 compound was greater than the MSTN control, we believe that ZINC85592908 has therapeutic potential against the MSTN protein and may hinder downstream singling by inhibiting the MSTN protein and increasing myogenesis in the skeletal muscle tissues.


Assuntos
Medicina Tradicional Chinesa , Doenças Musculares/tratamento farmacológico , Miostatina/antagonistas & inibidores , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Simulação de Dinâmica Molecular , Desenvolvimento Muscular/efeitos dos fármacos , Doenças Musculares/fisiopatologia , Ligação Proteica
10.
Molecules ; 27(9)2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35566383

RESUMO

Ralstonia solanacearum is among the most damaging bacterial phytopathogens with a wide number of hosts and a broad geographic distribution worldwide. The pathway of phenotype conversion (Phc) is operated by quorum-sensing signals and modulated through the (R)-methyl 3-hydroxypalmitate (3-OH PAME) in R. solanacearum. However, the molecular structures of the Phc pathway components are not yet established, and the structural consequences of 3-OH PAME on quorum sensing are not well studied. In this study, 3D structures of quorum-sensing proteins of the Phc pathway (PhcA and PhcR) were computationally modeled, followed by the virtual screening of the natural compounds library against the predicted active site residues of PhcA and PhcR proteins that could be employed in limiting signaling through 3-OH PAME. Two of the best scoring common ligands ZINC000014762512 and ZINC000011865192 for PhcA and PhcR were further analyzed utilizing orbital energies such as HOMO and LUMO, followed by molecular dynamics simulations of the complexes for 100 ns to determine the ligands binding stability. The findings indicate that ZINC000014762512 and ZINC000011865192 may be capable of inhibiting both PhcA and PhcR. We believe that, after further validation, these compounds may have the potential to disrupt bacterial quorum sensing and thus control this devastating phytopathogenic bacterial pathogen.


Assuntos
Ralstonia solanacearum , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Ligantes , Percepção de Quorum/genética
11.
Arch Microbiol ; 203(4): 1309-1320, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33325000

RESUMO

Lipase is an important commercial enzyme with unique and versatile biotechnological applications. This study was conducted to biosynthesize and characterizes alkaliphilic lipase by Exiguobacterium sp. strain AMBL-20T isolated from the glacial water samples of the northeastern (Gilgit-Baltistan) region of Pakistan. The isolated bacterium was identified as Exiguobaterium sp. strain AMBL-20T on the basis of morphological, biochemical, and phylogenetic analysis of 16S rRNA sequences with GenBank accession number MW229267. The bacterial strain was further screened for its lipolytic activity, biosynthesis, and characterization by different parameters with the aim of maximizing lipase activity. Results showed that 2% Olive oil, 0.2% peptone at 25 °C, pH 8, and 24 h of incubation time found optimal for maximum lipase production. The lipase enzyme was partially purified by ammonium sulphate precipitation and its activity was standardized at pH 8 under 30 °C temperature. The enzyme showed functional stability over a range of temperature and pH. Hence, extracellular alkaliphilic lipase from Exiguobacterium sp. is a potential candidate with extraordinary industrial applications, particularly in bio-detergent formulations.


Assuntos
Exiguobacterium/enzimologia , Camada de Gelo/microbiologia , Lipase/metabolismo , Estabilidade Enzimática , Exiguobacterium/classificação , Exiguobacterium/genética , Exiguobacterium/isolamento & purificação , Concentração de Íons de Hidrogênio , Lipase/isolamento & purificação , Lipólise , Paquistão , Filogenia , RNA Ribossômico 16S/genética , Temperatura
12.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809794

RESUMO

In recent years, a major rise in the demand for biotherapeutic drugs has centered on enhancing the quality and efficacy of cell culture and developing new cell culture techniques. Here, we report fibronectin (FN) derived, novel peptides fibronectin-based intergrin binding peptide (FNIN)2 (18-mer) and FNIN3 (20-mer) which promote cell adhesion proliferation, and the differentiation of primary cells and stem cells. FNIN2 and 3 were designed based on the in silico interaction studies between FN and its receptors (integrin α5ß1, αvß3, and αIIbß3). Analysis of the proliferation of seventeen-cell types showed that the effects of FNINs depend on their concentration and the existence of expressed integrins. Significant rhodamine-labeled FNIN2 fluorescence on the membranes of HeLa, HepG2, A498, and Du145 cells confirmed physical binding. Double coating with FNIN2 or 3 after polymerized dopamine (pDa) or polymerized tannic acid (pTA) precoating increased HBEpIC cell proliferation by 30-40 percent, suggesting FNINs potently affect primary cells. Furthermore, the proliferation of C2C12 myoblasts and human mesenchymal stem cells (MSCs) treated with FNINs was significantly increased in 2D/3D culture. FNINs also promoted MSC differentiation into osteoblasts. The results of this study offer a new approach to the production of core materials (e.g., cell culture medium components, scaffolds) for cell culture.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Fibronectinas/química , Células-Tronco Mesenquimais/citologia , Peptídeos/farmacologia , Alginatos , Animais , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células HeLa , Humanos , Integrinas/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Modelos Moleculares , Osteogênese/efeitos dos fármacos , Domínios Proteicos , Ratos , Receptores de Superfície Celular/metabolismo
13.
Int J Mol Sci ; 22(2)2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33467209

RESUMO

Skeletal muscle is the most abundant tissue and constitutes about 40% of total body mass. Herein, we report that crude water extract (CWE) of G. uralensis enhanced myoblast proliferation and differentiation. Pretreatment of mice with the CWE of G. uralensis prior to cardiotoxin-induced muscle injury was found to enhance muscle regeneration by inducing myogenic gene expression and downregulating myostatin expression. Furthermore, this extract reduced nitrotyrosine protein levels and atrophy-related gene expression. Of the five different fractions of the CWE of G. uralensis obtained, the ethyl acetate (EtOAc) fraction more significantly enhanced myoblast proliferation and differentiation than the other fractions. Ten bioactive compounds were isolated from the EtOAc fraction and characterized by GC-MS and NMR. Of these compounds (4-hydroxybenzoic acid, liquiritigenin, (R)-(-)-vestitol, isoliquiritigenin, medicarpin, tetrahydroxymethoxychalcone, licochalcone B, liquiritin, liquiritinapioside, and ononin), liquiritigenin, tetrahydroxymethoxychalcone, and licochalcone B were found to enhance myoblast proliferation and differentiation, and myofiber diameters in injured muscles were wider with the liquiritigenin than the non-treated one. Computational analysis showed these compounds are non-toxic and possess good drug-likeness properties. These findings suggest that G. uralensis-extracted components might be useful therapeutic agents for the management of muscle-associated diseases.


Assuntos
Glycyrrhiza uralensis/química , Atrofia Muscular/tratamento farmacológico , Extratos Vegetais/química , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Chalconas/química , Chalconas/farmacologia , Chalconas/uso terapêutico , Flavanonas/química , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Miostatina/genética , Miostatina/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Tirosina/análogos & derivados , Tirosina/metabolismo
14.
Molecules ; 26(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34500839

RESUMO

The skeletal muscle (SM) is the largest organ in the body and has tremendous regenerative power due to its myogenic stem cell population. Myostatin (MSTN), a protein produced by SM, is released into the bloodstream and is responsible for age-related reduced muscle fiber development. The objective of this study was to identify the natural compounds that inhibit MSTN with therapeutic potential for the management of age-related disorders, specifically muscle atrophy and sarcopenia. Sequential screening of 2000 natural compounds was performed, and dithymoquinone (DTQ) was found to inhibit MSTN with a binding free energy of -7.40 kcal/mol. Furthermore, the docking results showed that DTQ reduced the binding interaction between MSTN and its receptor, activin receptor type-2B (ActR2B). The global energy of MSTN-ActR2B was found to be reduced from -47.75 to -40.45 by DTQ. The stability of the DTQ-MSTN complex was subjected to a molecular dynamics analysis for up to 100 ns to check the stability of the complex using RMSD, RMSF, Rg, SASA, and H-bond number. The complex was found to be stable after 10 ns to the end of the simulation. These results suggest that DTQ blocks MSTN signaling through ActR2B and that it has potential use as a muscle growth-promoting agent during the aging process.


Assuntos
Benzoquinonas/química , Doenças Musculares/metabolismo , Miostatina/antagonistas & inibidores , Sarcopenia/metabolismo , Receptores de Activinas Tipo II/metabolismo , Sequência de Aminoácidos , Benzoquinonas/metabolismo , Benzoquinonas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Cinética , Simulação de Dinâmica Molecular , Fibras Musculares Esqueléticas , Doenças Musculares/tratamento farmacológico , Ligação Proteica , Conformação Proteica , Transdução de Sinais
15.
Molecules ; 26(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946559

RESUMO

Alzheimer's disease (AD) is the most common form of dementia and is characterized by irreversible and progressive neurodegeneration. Cholinergic dysfunction has been reported in AD, and several cholinesterase inhibitors, including natural compounds and synthetic analogs, have been developed to treat the disease. However, there is currently no treatment for AD, as most drug-like compounds have failed in clinical trials. Acetylcholinesterase (AChE) is the target of most drugs used commercially to treat AD. This work focused on screening natural compounds obtained from the ZINC database (224, 205 compounds) against AChE to identify those possibly capable of enabling the management of AD. Indirubin and dehydroevodiamine were the best potential AChE inhibitors with free binding energies of -10.03 and -9.00 kcal/mol, respectively. The key residue (His447) of the active site of AChE was found to participate in complex interactions with these two molecules. Six H-bonds were involved in the 'indirubin-AChE' interaction and three H-bonds in the 'dehydroevodiamine-AChE' interaction. These compounds were predicted to cross the blood-brain barrier (BBB) and to exhibit high levels of intestinal absorption. Furthermore, 'indirubin-AChE' and 'dehydroevodiamine-AChE' complexes were found to be stable, as determined by root mean square deviation (RMSD) during a 50 ns molecular dynamics simulation study. Based on the free binding energies and stabilities obtained by simulation studies, we recommend that experimental studies be undertaken on indirubin and dehydroevodiamine with a view towards their potential use as treatments for AD.


Assuntos
Acetilcolinesterase/química , Produtos Biológicos/química , Inibidores da Colinesterase/química , Biologia Computacional/métodos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Doença de Alzheimer/tratamento farmacológico , Sítios de Ligação , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/farmacologia , Bases de Dados de Produtos Farmacêuticos , Humanos , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade
16.
Molecules ; 26(3)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499241

RESUMO

The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium-glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2 inhibitor drugs are under evaluation due to their associative side effects, such as urinary tract and genital infection, urinary discomfort, diabetic ketosis, and kidney problems. Even clinicians have difficulty in recommending it to diabetic patients due to the increased probability of urinary tract infection. In our study, we selected natural SGLT2 inhibitors, namely acerogenin B, formononetin, (-)-kurarinone, (+)-pteryxin, and quinidine, to explore their potential against an emerging uropathogenic bacterial therapeutic target, i.e., FimH. FimH plays a critical role in the colonization of uropathogenic bacteria on the urinary tract surface. Thus, FimH antagonists show promising effects against uropathogenic bacterial strains via their targeting of FimH's adherence mechanism with less chance of resistance. The molecular docking results showed that, among natural SGLT2 inhibitors, formononetin, (+)-pteryxin, and quinidine have a strong interaction with FimH proteins, with binding energy (∆G) and inhibition constant (ki) values of -5.65 kcal/mol and 71.95 µM, -5.50 kcal/mol and 92.97 µM, and -5.70 kcal/mol and 66.40 µM, respectively. These interactions were better than those of the positive control heptyl α-d-mannopyranoside and far better than those of the SGLT2 inhibitor drug canagliflozin. Furthermore, a 50 ns molecular dynamics simulation was conducted to optimize the interaction, and the resulting complexes were found to be stable. Physicochemical property assessments predicted little toxicity and good drug-likeness properties for these three compounds. Therefore, formononetin, (+)-pteryxin, and quinidine can be proposed as promising SGLT2 inhibitors drugs, with add-on FimH inhibition potential that might reduce the probability of uropathogenic side effects.


Assuntos
Adesinas de Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/prevenção & controle , Proteínas de Fímbrias/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Infecções Urinárias/prevenção & controle , Escherichia coli Uropatogênica/efeitos dos fármacos , Adesinas de Escherichia coli/química , Biologia Computacional , Simulação por Computador , Cumarínicos/química , Cumarínicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Infecções por Escherichia coli/etiologia , Proteínas de Fímbrias/química , Humanos , Isoflavonas/química , Isoflavonas/farmacologia , Simulação de Acoplamento Molecular , Quinidina/química , Quinidina/farmacologia , Transportador 2 de Glucose-Sódio/química , Inibidores do Transportador 2 de Sódio-Glicose/química , Infecções Urinárias/etiologia , Escherichia coli Uropatogênica/patogenicidade
17.
Semin Cancer Biol ; 56: 1-11, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29248538

RESUMO

Extensive growth of cancer in humans is a major cause of death. Numerous studies are being conducted to improve the early diagnosis, prevention, and treatment of cancer. Recent technological advancements in medical science and research indicate molecular target therapy holds much promise in cancer treatment. In the past, therapeutic and diagnostic targeting of non-glycolytic and glycolytic enzymes in cancer have been successful, and discoveries of biomarker enzymes in cancer hold promise for therapeutic treatments. In this review, we discuss the roles of several cancer-associated enzymes that could potentially act as therapeutic targets, and place special focus on non-glycolytic and glycolytic enzymes. This review indicates that the targeting of metabolic signaling offers a promising means of developing novel anti-cancer therapies.


Assuntos
Biomarcadores Tumorais/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Animais , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Neoplasias/etiologia , Neoplasias/prevenção & controle
18.
Int J Mol Sci ; 21(11)2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32481704

RESUMO

The extracellular matrix (ECM) provides a scaffold for cells, controlling biological processes and providing structural as well as mechanical support to surrounding cells. Disruption of ECM homeostasis results in several pathological conditions. Skeletal muscle ECM is a complex network comprising collagens, proteoglycans, glycoproteins, and elastin. Recent therapeutic approaches targeting ECM remodeling have been extensively deliberated. Various ECM components are typically found to be augmented in the skeletal muscle of obese and/or diabetic humans. Skeletal muscle ECM remodeling is thought to be a feature of the pathogenic milieu allied with metabolic dysregulation, obesity, and eventual diabetes. This narrative review explores the current understanding of key components of skeletal muscle ECM and their specific roles in the regulation of metabolic diseases. Additionally, we discuss muscle-specific integrins and their role in the regulation of insulin sensitivity. A better understanding of the importance of skeletal muscle ECM remodeling, integrin signaling, and other factors that regulate insulin activity may help in the development of novel therapeutics for managing diabetes and other metabolic disorders.


Assuntos
Diabetes Mellitus/metabolismo , Matriz Extracelular/metabolismo , Doenças Metabólicas/metabolismo , Músculo Esquelético/metabolismo , Animais , Colágeno/metabolismo , Elastina/metabolismo , Homeostase , Humanos , Resistência à Insulina , Integrinas/metabolismo , Laminina/metabolismo , Camundongos , Ratos
19.
Molecules ; 25(9)2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32365525

RESUMO

Alzheimer's disease (AD) is the most common type of dementia and usually manifests as diminished episodic memory and cognitive functions. Caspases are crucial mediators of neuronal death in a number of neurodegenerative diseases, and caspase 8 is considered a major therapeutic target in the context of AD. In the present study, we performed a virtual screening of 200 natural compounds by molecular docking with respect to their abilities to bind with caspase 8. Among them, rutaecarpine was found to have the highest (negative) binding energy (-6.5 kcal/mol) and was further subjected to molecular dynamics (MD) simulation analysis. Caspase 8 was determined to interact with rutaecarpine through five amino acid residues, specifically Thr337, Lys353, Val354, Phe355, and Phe356, and two hydrogen bonds (ligand: H35-A: LYS353:O and A:PHE355: N-ligand: N5). Furthermore, a 50 ns MD simulation was conducted to optimize the interaction, to predict complex flexibility, and to investigate the stability of the caspase 8-rutaecarpine complex, which appeared to be quite stable. The obtained results propose that rutaecarpine could be a lead compound that bears remarkable anti-Alzheimer's potential against caspase 8.


Assuntos
Caspase 8/química , Inibidores de Caspase/química , Inibidores de Caspase/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Sítios de Ligação , Fenômenos Químicos , Humanos , Ligação de Hidrogênio , Ligantes , Ligação Proteica
20.
Semin Cancer Biol ; 49: 9-19, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29113952

RESUMO

Oxidative, carbonyl, and glycative stress have gained substantial attention recently for their alleged influence on cancer progression. Oxidative stress can trigger variable transcription factors, such as nuclear factor erythroid-2-related factor (Nrf2), nuclear factor kappa B (NF-κB), protein-53 (p-53), activating protein-1 (AP-1), hypoxia-inducible factor-1α (HIF-1α), ß-catenin/Wnt and peroxisome proliferator-activated receptor-γ (PPAR-γ). Activated transcription factors can lead to approximately 500 different alterations in gene expression, and can alter expression patterns of inflammatory cytokines, growth factors, regulatory cell cycle molecules, and anti-inflammatory molecules. These alterations of gene expression can induce a normal cell to become a tumor cell. Glycative stress resulting from advanced glycation end products (AGEs) and reactive dicarbonyls can significantly affect cancer progression. AGEs are fashioned from the multifaceted chemical reaction of reducing sugars with a compound containing an amino group. AGEs bind to and trigger the receptor for AGEs (RAGE) through AGE-RAGE interaction, which is a major modulator of inflammation allied tumors. Dicarbonyls like, GO (glyoxal), MG (methylglyoxal) and 3-DG (3-deoxyglucosone) fashioned throughout lipid peroxidation, glycolysis, and protein degradation are viewed as key precursors of AGEs. These dicarbonyls lead to the carbonyl stress in living organisms, possibly resulting in carbonyl impairment of proteins, carbohydrates, DNA, and lipoproteins. The damage caused by carbonyls results in numerous lesions, some of which are involved in cancer pathogenesis. In this review, the effects of oxidative, carbonyl and glycative stress on cancer initiation and progression are thoroughly discussed, including probable signaling pathways and the effects on tumorigenesis.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Neoplasias/metabolismo , Estresse Oxidativo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Animais , Glicosilação , Humanos , Inflamação/metabolismo , Masculino , Oxirredução , Fatores de Transcrição/metabolismo
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