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AIMS: Antibiotic resistance including multidrug resistance (MDR) is a negative symbol to the human health system because it loses the capability to treat infections. Unfortunately, the available antibiotics do not show an effective therapeutic response against bacterial infections. In the situation of global antibiotic unresponsiveness, enzymatic therapy especially in combinatorial form seems an effective approach to control bacterial infection and combat resistance. The article is important because it focuses on combinatorial enzymatic therapy that has multiple properties (effective antibacterial performances, antibiofilm capacity, immunomodulators, targeted actions, synergistic actions, multiple targeting, and resistance-proof properties) and can address antibiotic resistance effectively. MATERIALS AND METHODS: We searched the related topics with Pubmed, Scopus, and Google Scholar databases and finally 73 relevant papers were reviewed in detail and cited in this article. KEY FINDINGS: Discusses properties of combinatorial therapeutic enzymes made it an accomplished means over antibiotic therapy. This article discusses the need for combinatorial enzymatic therapy against bacterial infection, its distinguished features, and properties with multi-mechanistic antibacterial action. It discussed the European Medicine Agency and Food and Drug Administration-approved therapeutic enzymes (antibacterial and antibiofilm). SIGNIFICANCE: This article provided the possible combination of the enzyme that may be used as an antibacterial agent along with limitations and future scope of combinatorial antibacterial enzymatic agents. This article could draw the attention of researchers to combinatorial therapeutic enzymatic molecules as effective and futuristic therapy to overcome the problem of multiple antibiotic resistance in bacteria.
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Antibacterianos , Bacterias , Infecciones Bacterianas , Biopelículas , Farmacorresistencia Bacteriana Múltiple , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Humanos , Infecciones Bacterianas/tratamiento farmacológico , Bacterias/efectos de los fármacos , Biopelículas/efectos de los fármacos , Animales , Terapia Enzimática , Enzimas/metabolismo , Enzimas/farmacologíaRESUMEN
Fruits are a very good source of various nutrients that can boost overall human health. In these days, the recovery of therapeutic compounds from different fruit wastes is trending in research, which might not only minimize the waste problem but also encounter a higher demand for various enzymes that could have antimicrobial properties against infectious diseases. The goal of this review is to focus on the recovery of therapeutic enzymes from fruit wastes and its present-day tendency for utilization. Here we discussed different parts of fruit waste, such as pulp, pomace, seed, kernel, peel, etc., that produce therapeutic enzymes like amylase, cellulose, lipase, laccase, pectinase, etc. These bioactive enzymes are present in different parts of fruit and could be used as therapeutics against various infectious diseases. This article provides a thorough knowledge compilation of therapeutic enzyme isolation from fruit waste on a single platform, distinctly informative, and significant review work on the topic that is envisioned to encourage further research ideas in these areas that are still under-explored. This paper explains the various aspects of enzyme isolation from fruit and vegetable waste and their biotherapeutic potential that could provide new insights into the development of biotherapeutics and attract the attention of researchers to enhance translational research magnitude further.
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OBJECTIVES: Salmonella Typhibiofilm condition is showing as a major public health problem due to the development of antibiotic resistance and less available druggable target proteins. Therefore, we aimed to identify some more druggable targets of S. Typhibiofilm using computational drilling at the genome/proteome level so that the target shortage problem could be overcome and more antibiofilm agents could be designed in the future against the disease. METHODS: We performed protein-protein docking and interaction analysis between the homological identified target proteins of S.Typhi biofilm and a therapeutic protein L-Asparaginase. RESULTS: We have identified some druggable targets CsgD, BcsA, OmpR, CsgG, CsgE, and CsgF in S.Typhi. These targets showed high-binding affinity BcsA (-219.8 Kcal/mol) >csgF (-146.52 Kcal/mol) >ompR (-135.68 Kcal/mol) >CsgE (-134.66 Kcal/mol) >CsgG (-113.81 Kcal/mol) >CsgD(-95.39 Kcal/mol) with therapeutic enzyme L-Asparaginase through various hydrogen-bonds and salt-bridge. We found six proteins of S. Typhi biofilm from the Csg family as druggable multiple targets. CONCLUSION: This study provides insight into the idea of identification of new druggable targets and their multiple targeting with L-Asparaginase to overcome target shortage in S. Typhibiofilm-mediated infections. Results further indicated that L-Asparaginase could potentially be utilized as an antibiofilm biotherapeutic agent against S.Typhi.
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Antibacterianos , Asparaginasa , Biopelículas , Simulación del Acoplamiento Molecular , Salmonella typhi , Biopelículas/efectos de los fármacos , Asparaginasa/farmacología , Asparaginasa/aislamiento & purificación , Salmonella typhi/efectos de los fármacos , Humanos , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Diseño de Fármacos , Terapia Molecular Dirigida , Farmacorresistencia BacterianaRESUMEN
AIMS: Salmonella Typhi biofilm-mediated infections are globally rising. Due to the emergence of drug resistance antibiotics did not show effective results against S. Typhi biofilm. Therefore, there is an urgent need for an in-depth interrogation of S. Typhi biofilm to understand its formation kinetics, compositions, and surface charge value. METHODS: This study utilized the S. Typhi MTCC-733 strain from a microbial-type culture collection in India. The S. Typhi biofilm was formed on a glass slide in a biofilm development apparatus. Typhoidal biofilm analysis was done with the help of various assays such as a crystal violet assay, SEM analysis, FTIR analysis, Raman analysis, and zeta potential analysis. KEY FINDING: This article contained a comprehensive assessment of the typhoid biofilm formation kinetics, biofilm compositions, and surface charge which revealed that cellulose was a major molecule in the typhoidal biofilm which can be used as a major biofilm drug target against typhoidal biofilm. SIGNIFICANCE: This study provided interrogations about typhoidal biofilm kinetics which provided ideas about the biofilm composition. The cellulose molecule showed a major component of S. Typhi biofilm and it could potentially involved in drug resistance, and offer a promising avenue for developing a new antibiofilm therapeutic target to conquer the big obstacle of drug resistance. The obtained information can be instrumental in designing novel therapeutic molecules in the future to combat typhoidal biofilm conditions effectively for overcoming antibiotic resistance against bacterial infection Salmonella.
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Salmonella typhi , Fiebre Tifoidea , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana , Fiebre Tifoidea/tratamiento farmacológico , Fiebre Tifoidea/microbiología , Biopelículas , Celulosa , Pruebas de Sensibilidad MicrobianaRESUMEN
Tuberculosis (TB) caused by Mycobacterium tuberculosis is a lethal infectious disease that is prevalent worldwide. During TB infection, host microRNAs change their expression in the form of up/down-regulation. The identification of unique host microRNAs during TB could serve as potential biomarkers in the early detection of TB. microRNAs fulfill the required criteria for being an ideal biomarker, such as sensitivity, high specificity, and accessibility. Therefore, the recognition of potential host microRNAs can be valuable for the diagnosis of TB. The field of miRNA biomarkers in TB requires more extensive research to identify potential biomarkers. This review provides an overview of the biogenesis and biological functions of microRNAs and presents the findings of various studies on the identification of potential biomarkers for TB. Research momentum is gaining in this field and we anticipate that miRNAs will become a routine approach in the development of reliable diagnostic and specific therapeutic interventions in future.
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MicroARNs , Mycobacterium tuberculosis , Tuberculosis , Humanos , MicroARNs/genética , Patología Molecular , Tuberculosis/diagnóstico , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Biomarcadores/metabolismoRESUMEN
Background: Salmonella typhi biofilm confers a serious public health issue for lengthy periods and the rise in antibiotic resistance and death rate. Biofilm generation has rendered even the most potent antibiotics ineffective in controlling the illness, and the S. typhi outbreak has turned into a fatal disease typhoid. S. typhi infection has also been connected to other deadly illnesses, such as a gall bladder cancer. The virulence of this disease is due to the interaction of numerous genes and proteins of S. typhi. Objective: The study aimed to identify a cascade of target proteins in S. typhi biofilm condition with the help of genomic data mining and protein-protein interaction analysis. Methods: The goal of this study was to notice some important pharmacological targets in S. typhi. using genomic data mining, and protein-protein interaction approaches were used so that new drugs could be developed to combat the disease. Results: In this study, we identified 15 potential target proteins that are critical for S. typhi biofilm growth and maturation. Three proteins, CsgD, AdrA, and BcsA, were deciphered with their significant role in the synthesis of cellulose, a critical component of biofilm's extracellular matrix. The CsgD protein was also shown to have high interconnectedness and strong interactions with other important target proteins of S. typhi. As a result, it has been concluded that CsgD is involved in a range of activities, including cellulose synthesis, bacterial pathogenicity, quorum sensing, and bacterial virulence. Conclusion: All identified targets in this study possess hydrophobic properties, and their cellular localization offered proof of a potent therapeutic target. Overall results of this study, drug target shortage in S. typhi is also spotlighted, and we believe that obtained result could be useful for the design and development of some potent anti-salmonella agents for typhoid fever in the future.
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Globally, bacteria are well-known microorganisms for bacterial biofilm infection. Bacterial biofilm has generated antibiotic resistance and led the persistent infection. But new complications arise with a biofilm that bacterial biofilm shows the new association with oncogenesis. Some bacteria have a carcinogenic nature at the chronic infection stage like Salmonella Typhi, Helicobacter pylori. Thus, biofilm has a significant role in oncogenesis. Few pieces of evidence also support that the bacterial biofilm has a potential role to develop oncogenesis in the human body. Bacterial biofilm is responsible to induce chronic inflammation and is the main basis for the oncogenesis process. But bacterial biofilm association with the oncogenesis mechanism is unknown yet. This article focuses on the function of bacterial biofilm in tumor formation and the mechanism that encourages the oncogenesis and provide a possible and interesting hypothesis involved in between biofilm and host oncogenesis progression. The discussed relationship will provide a sound direction in the field of oncology and concept may give an informative direction in diagnosis and treatment. Bacterial biofilm behavior could be significantly linked with cancer cell formation. This article attracts the attention of researchers of the field because biofilm mediated oncogenesis further indicate towards an important issue in human health.
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Infecciones Bacterianas , Biopelículas , Humanos , Bacterias , Infecciones Bacterianas/tratamiento farmacológico , Farmacorresistencia Microbiana , Carcinogénesis , Antibacterianos/farmacologíaRESUMEN
Selenium-derived electrocatalysts have been well explored for electrocatalytic hydrogen evolution reactions to mimic hydrogenase-like activity; however, the stability of these synthetic mimics is yet to be enhanced. In this study, we report the synthesis and characterization of a series of 1,10-phenanthroline-cobalt(II) phenolate selenoether complexes using 1,10-phenanthroline and 6-nitro-1,10-phenanthroline-Co(II)-dichloride and substituted bis-selenophenolate ligands. The synthesized cobalt(II) phenolate selenoether complexes have been characterized by CHN analysis, mass spectrometry, single crystal XRD, and UV-visible absorption spectroscopy. These complexes show electrocatalytic proton reduction from acetic acid at an overpotential of 0.45-0.56 V vs. Fc+/Fc and surpass previously reported selenium and sulfur-containing electrocatalysts. Furthermore, gas analysis from control potential electrolysis confirms that the cobalt(II) selenoethers act as electrocatalysts to produce H2 with a faradaic efficiency of 43-83% and show a turnover number of 3.24-58.60 molcat-1. The hydrogen evolution reaction (HER) was probed using deuterated acetic acid, which demonstrates an inverse kinetic isotopic effect (KIE) and is consistent with the formation of metal hydride intermediates. Furthermore, control experiments (post-dip analysis and multiple CV studies) have been performed to support the catalysis being due to a homogeneous process. Acid titration using UV-visible spectroscopy reveals that protonation is the prior step for electrocatalysis and assists in the formation of a cobalt hydride intermediate, which upon reaction with a proton generates hydrogen gas.
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Hidrogenasas , Selenio , Protones , Hidrogenasas/química , Cobalto/química , Hidrógeno/químicaRESUMEN
Here, an α-selective Csp3-H bond functionalization of primary aliphatic alcohols with 1,4-naphthoquinones yielded Csp2-Csp2 coupled products driven by blue-LED light under catalyst, metal, base, and reagent-free conditions. In this transformation, cleavage of three C-H bonds (two sp3-C-H, one sp2-C-H, and one O-H) and four new bonds formed, leading to fluorescent 2-acylated-1,4-naphthohydroquinones.
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A one pot Cu(I)-assisted synthetic methodology has been developed for the preparation of biologically important C2-symmetric spirodiaza, benzyloxy and benzoxytelluranes from 2-bromo-N-aryl benzamides, benzyl alcohols, and benzoic acids by using the tellurium dianion (Te2-) under base-free conditions. Furthermore, C-C coupled biaryl 1,1'-diamides have been prepared by using an excess of Na2Te under the same reaction conditions. The synthesized spirodiazatelluranes served as a potent catalyst for the reduction of H2O2 and nitro-Michael reactions.
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Cobre , Telurio , Catálisis , Peróxido de Hidrógeno , IonesRESUMEN
Autophagy inhibition is currently considered a novel therapeutic strategy for cancer treatment. Lipoic acid (LA), a naturally occurring compound found in all prokaryotic and eukaryotic cells, inhibits breast cancer cell growth; however, the effect of LA on autophagy-mediated breast cancer cell death remains unknown. Our study identified that LA blocks autophagic flux by inhibiting autophagosome-lysosome fusion and lysosome activity which increases the accumulation of autophagosomes in MCF-7 and MDA-MB231 cells, leading to cell death of breast cancer cells. Interestingly, autophagic flux blockade limits the recycling of cellular fuels, resulting in insufficient substrates for cellular bioenergetics. Therefore, LA impairs cellular bioenergetics by the inhibition of mitochondrial function and glycolysis. We show that LA-induced ROS generation is responsible for the blockade of autophagic flux and cellular bioenergetics in breast cancer cells. Moreover, LA-mediated blockade of autophagic flux and ROS generation may interfere with the regulation of the BCSCs/progenitor phenotype. Here, we demonstrate that LA inhibits mammosphere formation and subpopulation of BCSCs. Together, these results implicate that LA acts as a prooxidant, potent autophagic flux inhibitor, and causes energetic impairment, which may lead to cell death in breast cancer cells/BCSCs.
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Neoplasias , Ácido Tióctico , Autofagosomas/metabolismo , Autofagia , Metabolismo Energético , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ácido Tióctico/farmacología , Ácido Tióctico/uso terapéuticoRESUMEN
Chalcogen-bonding interactions have recently gained considerable attention in the field of synthetic chemistry, structure, and bonding. Here, three organo-spiroselenuranes, having a Se(IV) center with a strong intramolecular Se···N chalcogen-bonded interaction, have been isolated by the oxidation of the respective bis(2-benzamide) selenides derived from an 8-aminoquinoline ligand. Further, the synthesized spiroselenuranes, when assayed for their antioxidant activity, show disproportionation of hydrogen peroxide into H2O and O2 with first-order kinetics with respect to H2O2 for the first time by any organoselenium molecules as monitored by 1H NMR spectroscopy. Electron-donating 5-methylthio-benzamide ring-substituted spiroselenurane disproportionates hydrogen peroxide at a high rate of 15.6 ± 0.4 × 103 µM min-1 with a rate constant of 8.57 ± 0.50 × 10-3 s-1, whereas 5-methoxy and unsubstituted-benzamide spiroselenuranes catalyzed the disproportionation of H2O2 at rates of 7.9 ± 0.3 × 103 and 2.9 ± 0.3 × 103 µM min-1 with rate constants of 1.16 ± 0.02 × 10-3 and 0.325 ± 0.025 × 10-3 s-1, respectively. The evolved oxygen gas from the spiroselenurane-catalyzed disproportion of H2O2 has also been confirmed by a gas chromatograph-thermal conductivity detector (GCTCD) and a portable digital polarographic dissolved O2 probe. Additionally, the synthesized spiroselenuranes exhibit thiol peroxidase antioxidant activities for the reduction of H2O2 by a benzenethiol co-reductant monitored by UV-visible spectroscopy. Next, the Se···N bonded spiroselenuranes have been explored as catalysts in synthetic oxidation iodolactonization and bromination of arenes. The synthesized spiroselenurane has activated I2 toward the iodolactonization of alkenoic acids under base-free conditions. Similarly, efficient chemo- and regioselective monobromination of various arenes with NBS catalyzed by chalcogen-bonded synthesized spiroselenuranes has been achieved. Mechanistic insight into the spiroselenuranes in oxidation reactions has been gained by 77Se NMR, mass spectrometry, UV-visible spectroscopy, single-crystal X-ray structure, and theoretical (DFT, NBO, and AIM) studies. It seems that the highly electrophilic nature of the selenium center is attributed to the presence of an intramolecular Se···N interaction and a vacant coordination site in spiroselenuranes is crucial for the activation of H2O2, I2, and NBS. The reaction of H2O2, I2, and NBS with tetravalent spiroselenurane would lead to an octahedral-Se(VI) intermediate, which is reduced back to Se(IV) due to thermodynamic instability of selenium in its highest oxidation state and the presence of a strong intramolecular N-donor atom.
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Peróxido de Hidrógeno , Selenio , Antioxidantes/química , Benzamidas , Catálisis , Peróxido de Hidrógeno/química , Oxidación-Reducción , Selenio/químicaRESUMEN
Phytophthora sp. are invasive groups of pathogens belonging to class Oomycetes. In order to contain and control them, a deep knowledge of their biology and infection strategy is imperative. With the availability of large-scale sequencing data, it has been possible to look directly into their genetic material and understand the strategies adopted by them for becoming successful pathogens. Here, we have studied the genomes of 128 Phytophthora species available publicly with reasonable quality. Our analysis reveals that the simple sequence repeats (SSRs) of all Phytophthora sp. follow distinct isolate specific patterns. We further show that TG/CA dinucleotide repeats are far more abundant in Phytophthora sp. than other classes of repeats. In case of tri- and tetranucleotide SSRs also, TG/CA-containing motifs always dominate over others. The GC content of the SSRs are stable without much variation across the isolates of Phytophthora. Telomeric repeats of Phytophthora follow a pattern of (TTTAGGG)n or (TTAGGGT)n rather than the canonical (TTAGGG)n. RxLR (arginine-any amino acid-leucine-arginine) motifs containing effectors diverge rapidly in Phytophthora and do not show any core common group. The RxLR effectors of some Phytophthora isolates have a tendency to form clusters with RxLRs from other species than within the same species. An analysis of the flanking intergenic distance clearly indicates a two-speed genome organization for all the Phytophthora isolates. Apart from effectors and the transposons, a large number of other virulence genes such as carbohydrate-active enzymes (CAZymes), transcriptional regulators, signal transduction genes, ATP-binding cassette transporters (ABC), and ubiquitins are also present in the repeat-rich compartments. This indicates a rapid co-evolution of this powerful arsenal for successful pathogenicity. Whole genome duplication studies indicate that the pattern followed is more specific to a geographic location. To conclude, the large-scale genomic studies of Phytophthora have thrown light on their adaptive evolution, which is largely guided by the localized host-mediated selection pressure.
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The development of alternative energy sources is the utmost priority of developing society. Unlike many prior homogeneous electrocatalysts that rely on a change in the oxidation state of the metal center and/or electrochemically active ligand, here we report the synthesis and structural characterization of a bimetallic zinc selenolate complex consisting of a redox silent zinc metal ion and a tridentate ligand that catalyzes the reduction of protons into hydrogen gas electrochemically and displays one of the highest reported TOF for a homogeneous TM-metal free ligand centered HER catalyst, 509 s-1. The current-voltage analysis confirms the onset overpotential of 0.86 V vs. Ag/AgCl for the HER process. Constant potential electrolysis (CPE) has been carried out to study the bulk electrolysis of our developed protocol, which reveals that the bimetallic zinc selenolate catalyst is stable under cathodic as well as anodic potentials and generates hydrogen gas with a faradaic efficiency of 75%. Preliminary studies on the heterogeneous catalyst were conducted by depositing the bimetallic zinc selenolate catalyst on the electrode surface.
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A series of novel copper(II) phenolate selenoether complexes have been synthesized and structurally characterized for the first time from copper(I) phenanthroline and various substituted ortho-bisphenylselenide-phenol chelating ligands. The synthesized complexes exhibit Jahn-Teller distortion in their geometry and varied from distorted square planar to distorted octahedral by varying the substituent in the bis-selenophenolate ligand. The synthesized complexes electrocatalyze the hydrogen evolution reaction (HER) with a faradaic efficiency of up to 89%, and it was observed that the distorted square pyramidal geometry is the optimum geometry for the maximum efficiency of these copper complexes.
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To date, organoseleniums are pre-eminent for peroxide decomposition and radical quenching antioxidant activities. On the contrary, here, a series of Janus-faced aminophenolic diselenides have been prepared from substituted 2-iodoaniline and selenium powder using copper-catalyzed methodology. Subsequently, condensation with substituted salicylaldehyde afforded the Schiff base, which on reduction, yielded the desired substituted aminophenolic diselenides in 72%-88% yields. The generation of reactive oxygen species (ROS) from oxygen gas by the synthesized aminophenolic diselenides was studied by analyzing the oxidation of dichlorofluorescein diacetate (DCFDA) dye and para-nitro-thiophenol by fluorescence and UV-Visible spectroscopic methods. Furthermore, density functional theory calculations and crystal structure analysis revealed the role of functional amine and hydroxyl sites present in the Janus-faced organoselenium catalyst for the activation of molecular oxygen, where NH and phenolic groups bring the oxygen molecule close to the catalyst by N-Hâ¯O and O-Hâ¯O intermolecular interactions. Additionally, these functionalities stabilize the selenium-centered radical in the formed transition states. Antioxidant activities of the synthesized diselenides have been explored as the catalyst for the decomposition of hydrogen peroxide using benzenethiol sacrificial co-reductant by a well-established thiol assay. Radical quenching antioxidant activity was studied by the quenching of DPPH radicals at 516 nm by UV-Visible spectroscopy. The structure activity correlation suggests that the electron-rich phenol and electron-rich and sterically hindered selenium center enhance the oxidizing property of the aminophenolic diselenides. Janus-faced diselenides were also evaluated for their cytotoxic effect on HeLa cancer cells via MTT assay, which suggests that the compounds are effective at 15-18 µM concentration against cancer cells. Moreover, the combination with therapeutic anticancer drugs Erlotinib and Doxorubicin showed promising cytotoxicity at the nanomolar concentration (8-28 nM), which is sufficient to suppress the growth of the cancer cells.
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Compuestos de OrganoselenioRESUMEN
The presence of a chalcogen atom at the ortho-position of phenols enhances their radical chain-breaking activity. Here, a copper(I)-catalyzed reaction of 2,6-dibromo- and 2,6-diiodophenols with diorganodiselenides has been studied for the introduction of two organoselenium substituents at both ortho-positions of the phenolic radical chain-breaking antioxidants, which afforded 2,6-diorganoseleno-substituted phenols in 80-92% yields having electron-donating CH3 , and electron-withdrawing CN and CHO functionalities. Additionally, 2,6-diiodophenols with electron-withdrawing CHO and CN groups also afforded novel 5,5'-selenobis(4-hydroxy-3-(phenylselanyl)benzaldehyde) and 5,5'-selenobis(4-hydroxy-3-(phenylselanyl)benzonitrile) consisting of three selenium and two phenolic moieties along with 2,6-diorganoseleno-substituted phenols has been synthesized. The electron-withdrawing CHO group has been reduced by sodium borohydride to the electron-donating alcohol CH2 OH group, which is desirable for efficient radical quenching activity of phenols. The developed copper-catalyzed reaction conditions enable the installation of two-arylselenium group ortho to phenolic radical chain-breaking antioxidants, which may not be possible by conventional organolithium-bromine exchange methods due to the sluggish reactivity of trianions (dicarba and phenoxide anion), which are generated by the reaction of organolithium with 2,6-dibromophenols, with diorganodiselenides. The antioxidant activities of the synthesized bis and tris selenophenols have been accessed by DPPH, thiol peroxides, and singlet oxygen quenching assay. The radical quenching antioxidant activity has been studied for the synthesized compounds by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The bis-selenophenols show comparable radical deactivating activity, while tris seleno-bisphenols show higher radical deactivating activity than α-tocopherol. Furthermore, the tris seleno-bisphenol shows comparable peroxide decomposing activity with ebselen molecules.
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Non-alcoholic fatty liver disease (NAFLD) is one the fastest emerging manifestations of the metabolic syndrome worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, may culminate into cirrhosis and hepatocellular cancer (HCC) and is presently a leading cause of liver transplant. Although a steady progress is seen in understanding of the disease epidemiology, pathogenesis and identifying therapeutic targets, the slowest advancement is seen in the therapeutic field. Currently, there is no FDA approved therapy for this disease and appropriate therapeutic targets are urgently warranted. In this review we discuss the role of lifestyle intervention, pharmacological agents, surgical approaches, and gut microbiome, with regard to therapy for NASH. In particular, we focus the role of insulin sensitizers, thyroid hormone mimetics, antioxidants, cholesterol lowering drugs, incretins and cytokines as therapeutic targets for NASH. We highlight these targets aiming to optimize the future for NASH therapy.
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Enfermedad del Hígado Graso no Alcohólico/terapia , Carcinoma Hepatocelular/patología , Progresión de la Enfermedad , Microbioma Gastrointestinal , Humanos , Estilo de Vida , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/cirugíaRESUMEN
Maternal inflammation ensuing from high-fat diet (HFD) intake during pregnancy is related to spontaneous preterm birth and respiratory impairment among premature infants. Recently, a circadian aligned dietary intervention referred to as Time-restricted feeding (TRF) has been reported to have beneficial metabolic effects. This study aimed to assess the effects of maternal TRF on fetal lung injury caused by maternal HFD intake. Female Wistar rats were kept on following three dietary regimens; Ad libitum normal chow diet (NCD-AL), Ad libitum HFD (HFD-AL) and Time-restricted fed HFD (HFD-TRF) from 5 months before mating and continued through pregnancy. Fetal lung samples were collected on the embryonic day 18.5, and apoptotic and inflammatory markers were assessed using TUNEL assay, western blotting, and qRT-PCR. Our results showed that TRF considerably prevented maternal HFD-induced apoptosis in fetal lung tissue that corroborated with a reduction in caspase activation and increased levels of anti-apoptotic BCL2 family proteins together with a lower level of ER-stress and autophagy markers including ATF6, CHOP and LC3-II. Besides, fetal lungs from HFD-TRF dams exhibited reduced expression of inflammatory genes that correlated with reduction and apoptotic injury throughout fetal development. Our results thus put forth TRF as a unique non-pharmacological approach to boost perinatal health beneath metabolic stress.
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Dieta Alta en Grasa/efectos adversos , Inflamación/prevención & control , Lesión Pulmonar/prevención & control , Relaciones Materno-Fetales , Animales , Peso Corporal , Femenino , Feto/fisiopatología , Humanos , Inflamación/etiología , Inflamación/fisiopatología , Pulmón/fisiopatología , Lesión Pulmonar/etiología , Lesión Pulmonar/fisiopatología , Ratones , Embarazo , Ratas , Ratas Wistar , Estrés Fisiológico/genética , Estrés Fisiológico/fisiologíaRESUMEN
The serine/threonine Protein Phosphatase 2A (PP2A) functions as a tumor suppressor by negatively regulating multiple oncogenic signaling pathways. The canonical PP2A holoenzyme comprises a scaffolding subunit (PP2A Aα/ß), which serves as the platform for binding of both the catalytic C subunit and one regulatory B subunit. Somatic heterozygous missense mutations in PPP2R1A, the gene encoding the PP2A Aα scaffolding subunit, have been identified across multiple cancer types, but the effects of the most commonly mutated residue, Arg-183, on PP2A function have yet to be fully elucidated. In this study, we used a series of cellular and in vivo models and discovered that the most frequent Aα R183W mutation formed alternative holoenzymes by binding of different PP2A regulatory subunits compared with wild-type Aα, suggesting a rededication of PP2A functions. Unlike wild-type Aα, which suppressed tumorigenesis, the R183W mutant failed to suppress tumor growth in vivo through activation of the MAPK pathway in RAS-mutant transformed cells. Furthermore, cells expressing R183W were less sensitive to MEK inhibitors. Taken together, our results demonstrate that the R183W mutation in PP2A Aα scaffold abrogates the tumor suppressive actions of PP2A, thereby potentiating oncogenic signaling and reducing drug sensitivity of RAS-mutant cells.