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1.
Ecotoxicol Environ Saf ; 286: 117216, 2024 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-39437518

RESUMO

Cadmium (Cd) has adverse effects on organisms. Serine is an essential nutritional factor and its nutritional value is extremely high for body. To explore the effects of serine on spleen toxicity induced by Cd in mice, cadmium chloride (CdCl2, 50 mg/L) and serine (50 g/L) were individually administered or co-administrated in drinking water of mice for 18 weeks. Results demonstrated that Cd exposure induced splenic toxicity and serine against the toxicity damage caused by Cd in mice. Under Cd stress, trace element homeostasis was disturbed, the mice's body weight and spleen index were increased, and splenic morphology and ultrastructure were altered. Furthermore, Cd exposure led to the cell populations disorder, which in turn triggers cell death. Notably, Cd treatment induced oxidative stress and inflammation, increased M1/M2 (iNOS, CD68) and Th1/Th2 (T-bet, CD4) levels, decreased M1/M2 (Arg1) and Th1/Th2 (GATA3) levels, while disrupted the macrophages and lymphocytes homeostasis, which trigged apoptosis and pyroptosis in spleen. In contrast, serine supplementation changed the levels of Cd and other elements, weakened Cd-induced tissue damage and inflammation, enhanced antioxidant capacity, significantly restored cell homeostasis, and effectively inhibited Cd-induced apoptosis and pyroptosis in the spleen. Shortly, the results verified that serine had an ameliorating toxicity effect and restored the M1/M2 and Th1/Th2 balance, restrained apoptosis and pyroptosis induced by Cd.

2.
Cell Mol Biol Lett ; 28(1): 87, 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37884867

RESUMO

Mitochondrial transfer regulates intercellular communication, and mitochondria regulate cell metabolism and cell survival. However, the role and mechanism of mitochondrial transfer in Cd-induced nonalcoholic fatty liver disease (NAFLD) are unclear. The present study shows that mitochondria can be transferred between hepatocytes via microtubule-dependent tunneling nanotubes. After Cd treatment, mitochondria exhibit perinuclear aggregation in hepatocytes and blocked intercellular mitochondrial transfer. The different movement directions of mitochondria depend on their interaction with different motor proteins. The results show that Cd destroys the mitochondria-kinesin interaction, thus inhibiting mitochondrial transfer. Moreover, Cd increases the interaction of P62 with Dynactin1, promotes negative mitochondrial transport, and increases intracellular lipid accumulation. Mitochondria and hepatocyte co-culture significantly reduced Cd damage to hepatocytes and lipid accumulation. Thus, Cd blocks intercellular mitochondrial transfer by disrupting the microtubule system, inhibiting mitochondrial positive transport, and promoting their negative transport, thereby promoting the development of NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Cádmio , Metabolismo dos Lipídeos , Mitocôndrias/metabolismo , Hepatócitos/metabolismo , Lipídeos , Fígado
3.
Int J Mol Sci ; 24(2)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36674718

RESUMO

Our previous studies have confirmed that cadmium (Cd) exposure causes hepatotoxicity; it also induces autophagy and blocks the autophagy flux. Therefore, we hypothesized that Cd hepatotoxicity could be alleviated through nutritional intervention. Taurine (Tau) has various biological functions such as acting as an antioxidant, acting as an anti-inflammatory, and stabilizing cell membranes. In order to explore the protective effect and internal mechanism of Tau on Cd-induced hepatotoxicity, normal rat liver cell line BRL3A cells were treated with Cd alone or in combination with Tau to detect cell injury and autophagy-related indexes in this study. We found that Tau can alleviate Cd-induced cell-proliferation decline and morphological changes in the cell. In addition, Tau activates autophagy and alleviates the blockage of Cd-induced autophagy flux. In this process, lysosome acidification and degradation were enhanced, and autophagosomes were further fused with lysosomes. Then, we found that Tau alleviated autophagic flux block by promoting the transfer of membrane fusion proteins STX17 and SNAP29 to autophagosomes and the translocation of VAMP8 to lysosomes, which in turn attenuated the hepatocyte injury induced by Cd exposure. This will further reveal the hepatotoxicity mechanism of Cd and provide the theoretical basis for the prevention and treatment of Cd poisoning.


Assuntos
Cádmio , Doença Hepática Induzida por Substâncias e Drogas , Ratos , Animais , Cádmio/metabolismo , Autofagia , Autofagossomos/metabolismo , Linhagem Celular , Lisossomos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo
4.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675029

RESUMO

Osteoprotegerin (OPG) is a new member of the tumor necrosis factor (TNF) receptor superfamily, which can inhibit the differentiation and activity of osteoclasts by binding to nuclear factor kappa B receptor activator (RANK) competitively with nuclear factor kappa B receptor activator ligand (RANKL). The previous experiments found that OPG can induce apoptosis of mature osteoclasts in vitro, which can inhibit the activity of mature osteoclasts, thereby exerting its role in protecting bone tissue. In addition, pyroptosis is a new type of cell death that is different from apoptosis. It is unclear whether OPG can induce mature osteoclast pyroptosis and thereby play its role in protecting bone tissue. In this study, the results showed that compared with the control group, the survival rate of osteoclasts in the OPG group was significantly reduced, and the contents of IL-1ß, IL-18, and LDH in the supernatant both increased. Many osteoclast plasma membranes were observed to rupture in bright fields, and OPG induced loss of their morphology. Flow cytometry was used to analyze the pyroptosis rate; OPG significantly increased the osteoclast pyroptosis rate. To further reveal the mechanism of OPG-induced osteoclast pyroptosis, we examined the expression level of pyroptosis-related genes and proteins, and the results found that OPG increased the expression of NLRP3, ASC, caspase-1, and GSDMD-N compared with the control group. In summary, OPG can induce osteoclast pyroptosis, and its mechanism is related to the expression levels of ASC, NLRP3, caspase 1 and GSDMD, which were included in the classical pathway of pyroptosis.


Assuntos
Osteoclastos , Osteoprotegerina , Osteoclastos/metabolismo , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Glicoproteínas/metabolismo , Glicoproteínas de Membrana/genética , NF-kappa B/metabolismo , Piroptose , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteoblastos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Ligante RANK/metabolismo
5.
J Transl Med ; 19(1): 218, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34030700

RESUMO

BACKGROUND: Post-translational modification (PTM) is a biological process that alters proteins and is therefore involved in the regulation of various cellular activities and pathogenesis. Protein phosphorylation is an essential process and one of the most-studied PTMs: it occurs when a phosphate group is added to serine (Ser, S), threonine (Thr, T), or tyrosine (Tyr, Y) residue. Dysregulation of protein phosphorylation can lead to various diseases-most commonly neurological disorders, Alzheimer's disease, and Parkinson's disease-thus necessitating the prediction of S/T/Y residues that can be phosphorylated in an uncharacterized amino acid sequence. Despite a surplus of sequencing data, current experimental methods of PTM prediction are time-consuming, costly, and error-prone, so a number of computational methods have been proposed to replace them. However, phosphorylation prediction remains limited, owing to substrate specificity, performance, and the diversity of its features. METHODS: In the present study we propose machine-learning-based predictors that use the physicochemical, sequence, structural, and functional information of proteins to classify S/T/Y phosphorylation sites. Rigorous feature selection, the minimum redundancy/maximum relevance approach, and the symmetrical uncertainty method were employed to extract the most informative features to train the models. RESULTS: The RF and SVM models generated using diverse feature types in the present study were highly accurate as is evident from good values for different statistical measures. Moreover, independent test sets and benchmark validations indicated that the proposed method clearly outperformed the existing methods, demonstrating its ability to accurately predict protein phosphorylation. CONCLUSIONS: The results obtained in the present work indicate that the proposed computational methodology can be effectively used for predicting putative phosphorylation sites further facilitating discovery of various biological processes mechanisms.


Assuntos
Biologia Computacional , Aprendizado de Máquina , Sequência de Aminoácidos , Fosforilação , Proteínas
6.
Drug Dev Ind Pharm ; 47(1): 12-21, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33190552

RESUMO

OBJECTIVE: The poly D, L-Lactic-co-glycolic acid (PLGA) and Polycaprolactone (PCL) have been widely applied for developing the prolonged-release formulation. The current study explores the application of these polymers for developing prolonged-release nanosphere of Duloxetine (DLX). Developing a prolonged release parenteral nanosphere formulation of DLX would be overcoming pitfalls like acid-labile degradation, first-pass metabolism and erratic bioavailability along with long-term therapeutic benefit in the treatment of depression. METHODS: DLX-loaded PLGA and PCL nanospheres were prepared by using the emulsion solvent evaporation technique. The developed formulation was compared with DLX oral solution concerning brain estimation. The prepared nanospheres were subjected to the morphology of the drug particles, polydispersity Index (PDI), distribution size, zeta potential, entrapment efficiency and percentage yield to generate a proof of concept. RESULTS: DLX-loaded polymeric nanosphere exhibited the uniform size from 89.48 nm to 100.9 nm. The entrapment efficiency was in the range of 74.93 to 77.49, respectively, of PLGA and PCL formulation. The FSEM image affirmed smooth spherical morphology. A good PDI and negative zeta potential value (-31.3 mV for F1 and -30.7 mV for F2) supported the stability of the nanosphere. The brain concentration of the drug was three times enhanced supporting the effectiveness of the nanosphere during pharmacodynamic and pharmacokinetic studies. CONCLUSION: The intramuscular DLX-loaded nanospheres signify improved brain availability relative to DLX solution. This can be a blueprint for the effective and targeted brain delivery of CNS drugs.


Assuntos
Cloridrato de Duloxetina/química , Nanopartículas , Nanosferas , Portadores de Fármacos , Ácido Láctico/química , Polímeros/química
7.
J Transl Med ; 17(1): 171, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118067

RESUMO

BACKGROUND: Predicting adverse drug reactions (ADRs) has become very important owing to the huge global health burden and failure of drugs. This indicates a need for prior prediction of probable ADRs in preclinical stages which can improve drug failures and reduce the time and cost of development thus providing efficient and safer therapeutic options for patients. Though several approaches have been put forward for in silico ADR prediction, there is still room for improvement. METHODS: In the present work, we have used machine learning based approach for cardiovascular (CV) ADRs prediction by integrating different features of drugs, biological (drug transporters, targets and enzymes), chemical (substructure fingerprints) and phenotypic (therapeutic indications and other identified ADRs), and their two and three level combinations. To recognize quality and important features, we used minimum redundancy maximum relevance approach while synthetic minority over-sampling technique balancing method was used to introduce a balance in the training sets. RESULTS: This is a rigorous and comprehensive study which involved the generation of a total of 504 computational models for 36 CV ADRs using two state-of-the-art machine-learning algorithms: random forest and sequential minimization optimization. All the models had an accuracy of around 90% and the biological and chemical features models were more informative as compared to the models generated using chemical features. CONCLUSIONS: The results obtained demonstrated that the predictive models generated in the present study were highly accurate, and the phenotypic information of the drugs played the most important role in drug ADRs prediction. Furthermore, the results also showed that using the proposed method, different drugs properties can be combined to build computational predictive models which can effectively predict potential ADRs during early stages of drug development.


Assuntos
Fármacos Cardiovasculares/efeitos adversos , Simulação por Computador , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Algoritmos , Bases de Dados como Assunto , Humanos , Aprendizado de Máquina , Fenótipo , Reprodutibilidade dos Testes
8.
Microb Pathog ; 123: 60-67, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29959039

RESUMO

It is conceivable that early developing germ cells must across the basal to the luminal region of seminiferous tubules (STs) during spermatogenesis is associated with extensive restructuring of junctional complex. However, very limited information is documented about these junctional complexes in reptiles. In the present study we have determined the localization of inter-Sertoli cell tight junctions (TJ's), protein CLDN11 and gap junction protein Cx43 during spermatogenesis in the testis. In early spermatogenesis, weak immunoreactivity of CLDN11and focal localization of Cx43 was observed around the Sertoli cell in the luminal region, but completely delaminated from the basal compartment of STs. In late spermatogenesis, strong focal to linear localization of CLDN11and Cx43 was detected at the points of contact between two Sertoli cells and around the early stages of primary spermatocytes in the basal compartment of STs. In late spermatogenesis, localization of CLDN11and Cx43 was drastically reduced and seen only around Sertoli cells and spermatogonia near the basal lamina. However, transmission electron microscopy revealed that inter-Sertoli cell tight junctions were present within the basal compartment of STs, leaving the spermatogonia and early primary spermatocytes in the basal region during mid spermatogenesis. Gap junctions were observed between Sertoli cells, and Sertoli cells with spermatogonia and primary spermatocytes throughout spermatogenesis. Moreover, adherens and hemidesmosomes junctions were observed during spermatogenesis. The above findings collectively suggest that the intensity and localization of TJ's and gap junctions vary according to the spermatogenetic stages that might be protected the developing germ cells from own immune response.


Assuntos
Junções Aderentes/fisiologia , Autoimunidade/imunologia , Hemidesmossomos/fisiologia , Células de Sertoli/citologia , Células de Sertoli/imunologia , Espermatogênese/fisiologia , Junções Íntimas/fisiologia , Animais , Claudinas/metabolismo , Conexina 43/metabolismo , Masculino , Microscopia Eletrônica de Transmissão , Espermatócitos/fisiologia , Espermatogônias/fisiologia , Tartarugas
9.
Poult Sci ; 103(11): 104242, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39255638

RESUMO

Environmental pollution poses a significant challenge to the poultry industry, leading to substantial losses and adverse effects on the health, production, and performance of avian species. In recent years, there has been growing interest in exploring natural compounds with potential protective effects against cadmium (Cd)-induced toxicity. Luteolin (LUT), a flavonoid found in various plants, has been studied for its antioxidant, anti-inflammatory, and cytoprotective properties. In this study, Su green shell grass chickens were divided into 4 groups: control, LUT (150 mg LUT), Cd (100 mg CdCl2), and Cd + LUT (100 mg CdCl2 + 150 mg LUT) groups for 1 month, respectively. The present study revealed that LUT maintained the morphology and functional activity of the liver and intestine. LUT alleviated Cd-induced impairment in the liver and intestinal biochemical indicators, suppressed Cd-induced liver fibrosis, mitigated liver and intestinal tissue damage. Additionally, LUT reduced oxidative stress and regulated the Cd-induced impairment in trace elements of the liver and intestine. Furthermore, LUT reduced Cd-induced liver inflammation, restored Cd-induced intestinal barrier function, and normalized Cd-induced serum proteins, including changes in the content of glutamyltranspeptidase. Moreover, LUT maintained Cd-induced disruption of gut microbiota and alleviated bacterial dysbiosis. Overall, these findings suggest that LUT holds promise as a potential therapeutic agent for mitigating the adverse effects of Cd-induced toxicity in poultry, by preserving liver and intestinal health, reducing oxidative stress, inflammation, and restoring gut microbiota balance.


Assuntos
Cádmio , Galinhas , Fígado , Luteolina , Animais , Luteolina/farmacologia , Luteolina/administração & dosagem , Cádmio/toxicidade , Fígado/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Doenças das Aves Domésticas/induzido quimicamente , Doenças das Aves Domésticas/prevenção & controle , Substâncias Protetoras/farmacologia , Substâncias Protetoras/administração & dosagem , Ração Animal/análise , Masculino , Dieta/veterinária , Estresse Oxidativo/efeitos dos fármacos
10.
Sci Total Environ ; 933: 173032, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38734099

RESUMO

Ferroptosis is frequently observed in fibrosis and diseases related to iron metabolism disorders in various mammalian organs. However, research regarding the damage mechanism of ferroptosis in the female reproductive system of avian species remains unclear. In this study, Muscovy female ducks were divided into three groups which were given purified water, 1 mg/L polyvinyl chloride microplastics (PVC-MPs) and 10 mg/L PVC-MPs for two months respectively, to investigate the ferroptosis induced by PVC-MPs caused ovarian tissue fibrosis that lead to premature ovarian failure. The results showed that the high accumulation of PVC-MPs in ovarian tissue affected the morphology and functional activity of ovarian granulosa cells (GCs) and subsequently caused the follicular development disorders and down-regulated the immunosignaling of ovarian steroidogenesis proteins 3ß-hydroxysteroid dehydrogenase (3ß-HSD), 17ß-hydroxysteroid dehydrogenase (17ß-HSD), CYP11A1 cytochrome (P450-11A1) and CYP17A1 cytochrome (P450-17A1) suggested impaired ovarian function. In addition, PVC-MPs significantly up-regulated positive expression of collagen fibers, significantly increased lipid peroxidation and malondialdehyde (MDA) level, along with encouraged overload of iron contents in the ovarian tissue were the characteristics of ferroptosis. Further, immunohistochemistry results confirmed that immunosignaling of ferroptosis related proteins Acyl-CoA synthetase (ACSL4), Cyclooxygenase 2 (COX2) and ferritin heavy chain 1 (FTH1) were significantly increased, but solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase (GPX4) were decreased by PVC-MPs in the ovarian tissue. In conclusion, our study demonstrates that PVC-MPs induced ferroptosis in the ovarian GCs, leading to follicle development disorders and ovarian tissue fibrosis, and ultimately contributing to various female reproductive disorders through regulating the proteins expression of ferroptosis.


Assuntos
Patos , Ferroptose , Microplásticos , Ovário , Cloreto de Polivinila , Animais , Feminino , Ferroptose/efeitos dos fármacos , Cloreto de Polivinila/toxicidade , Ovário/efeitos dos fármacos , Microplásticos/toxicidade , Poluentes Químicos da Água/toxicidade , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo
11.
Antioxidants (Basel) ; 13(1)2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38247538

RESUMO

Cadmium (Cd) is a major health concern globally and can accumulate and cause damage in the liver for which there is no approved treatment. Baicalin and N-acetylcysteine (NAC) have been found to have protective effects against a variety of liver injuries, but it is not clear whether their combined use is effective in preventing and treating Cd-induced lipid accumulation. The study found that Cd increased the production of mitochondrial reactive oxygen species (mROS) and elevated the level of chaperone-mediated autophagy (CMA). Interestingly, mROS-mediated CMA exacerbates the Cd-induced inhibition of lipophagy. Baicalin and NAC counteracted inhibition of lipophagy by attenuating Cd-induced CMA, suggesting an interplay between CMA elevation, mitochondrial destruction, and mROS formation. Maintaining the stability of mitochondrial structure and function is essential for alleviating Cd-induced lipid accumulation in the liver. Choline is an essential component of the mitochondrial membrane and is responsible for maintaining its structure and function. Mitochondrial transcriptional factor A (TFAM) is involved in mitochondrial DNA transcriptional activation and replication. Our study revealed that the combination of baicalin and NAC can regulate choline metabolism through TFAM and thereby maintain mitochondrial structure and functionality. In summary, the combination of baicalin and NAC plays a more beneficial role in alleviating Cd-induced lipid accumulation than the drug alone, and the combination of baicalin and NAC can stabilize mitochondrial structure and function and inhibit mROS-mediated CMA through TFAM-choline, thereby promoting lipophagy to alleviate Cd-induced lipid accumulation.

12.
J Exp Zool A Ecol Integr Physiol ; 341(1): 99-106, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37905465

RESUMO

Mitochondrial-rich cells (MRCs) are one of the most significant canceled type of epithelial cells. Morphologically these cells are totally different from other epithelial cells. These cells primarily implicated in sea-water and fresh-water adaptation, and acid-base regulation. However, in this review paper, we explored some of the most intriguing biological and immune-related functional developmental networks of MRCs. The main pinpoint, MRCs perform a dynamic osmoregulatory and immunological functional role in the gut and male reproductive system. The Na+/K+_ATPase (NKA) and Na+/K+/2Cl cotransporter (NKCC) are key acidifying proteins of MRCs for the ion-transporting function for intestinal homeostasis and maintenance of acidifying the luminal microenvironment in the male reproductive system. Further more importantly, MRCs play a novel immunological role through the exocrine secretion of nano-scale exosomes and multivesicular bodies (MVBs) pathway, which is very essential for sperm maturation, motility, acrosome reaction, and male sex hormones, and these an essential events to produce male gametes with optimal fertilizing ability. This effort is expected to promote the novel immunological role of MRCs, which might be essential for nano-scale exosome secretion.


Assuntos
Sêmen , Equilíbrio Hidroeletrolítico , Masculino , Animais , Sêmen/metabolismo , Osmorregulação , Mitocôndrias/metabolismo , Água/metabolismo
13.
Poult Sci ; 103(11): 104152, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39182342

RESUMO

A recently discovered environmental contaminant, microplastics (MP) are capable of amassing within the body and pose a grave threat to the health of both humans and animals. It is widely acknowledged that the combination of cadmium (Cd), a hazardous heavy metal, and microplastics produces synergistic deleterious effects. Nevertheless, the mechanism by which co-exposure to polyvinyl chloride microplastics (PVC-MP) and Cd damages the liver of avian females is unknown. Globally prevalent and the subject of extensive research in mammals, nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition. However, the mechanisms underlying injury to the avian digestive system caused by NAFLD remain unknown. Two months of co-exposure to Cd and PVC-MPs, pure water, solitary Cd exposure, single microplastics exposure, and pure water were administered to female Muscovy ducks in this study. The objective of this research was to examine whether the co-exposure of duck liver to PVC-MPs and Cd-induced oxidative stress resulted in NAFLD and subsequent apoptosis of hepatic cells. The study's findings showed that hepatocyte shape and functional activity were negatively impacted by PVC-MP and Cd buildup in liver tissues. Reduced liver organ coefficients, increased alanine aminotransferase (ALT) content, and ultrastructural damage to hepatocyte nuclei and mitochondria are indicators of this. These results point to a possible impairment in liver function. phosphoenolpyruvate carboxykinase 1 (PCK1) deficiency activates the protein kinase B/phosphatidylinositol 3-kinase (PI3K/AKT) pathway in the livers of female reproductive ducks that have been damaged by oxidative stress. This stimulation induces lipid deposition, fibrosis, and glycogen accumulation, which ultimately results in hepatocyte apoptosis. In summary, our research provides evidence that PVC-MPs cause oxidative harm to the liver, which subsequently results in fibrosis of liver tissue, hepatic glucolipid metabolism, and ultimately apoptosis.


Assuntos
Cádmio , Patos , Microplásticos , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo , Cloreto de Polivinila , Animais , Feminino , Estresse Oxidativo/efeitos dos fármacos , Cádmio/toxicidade , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Microplásticos/toxicidade , Glicolipídeos/metabolismo , Doenças das Aves Domésticas/induzido quimicamente , Fígado/efeitos dos fármacos , Fígado/metabolismo , Apoptose/efeitos dos fármacos
14.
Chem Biol Interact ; 394: 110976, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38552764

RESUMO

It is widely accepted that humans are constantly exposed to micro-plastics and nano-plastics through various routes, including inhalation of airborne particles, exposure to dust, and consumption of food and water. It is estimated that humans may consume thousand to millions of micro-plastic particles, equating to several milligrams per day. Prolonged exposure to micro-plastics and nano-plastics has been linked to negative effects on different living organisms, including neurotoxicity, gastrointestinal toxicity, nephrotoxicity, and hepatotoxicity, and developmental toxicities. The main purpose of this review is to explore the effect of micro-plastics and nano-plastics on the male and female reproductive system, as well as their offspring, and the associated mechanism implicated in the reproductive and developmental toxicities. Micro-plastics and nano-plastics have been shown to exert negative effects on the reproductive system of both male and female mammals and aquatic animals, including developmental impacts on gonads, gametes, embryo, and their subsequent generation. In addition, micro-plastics and nano-plastics impact the hypothalamic-pituitary axes, leading to oxidative stress, reproductive toxicity, neurotoxicity, cytotoxicity, developmental abnormalities, poor sperm quality, diminishes ovarian ovulation and immune toxicity. This study discusses the so many different signaling pathways associated in the male and female reproductive and developmental toxicity induced by micro-plastics and nano-plastics.


Assuntos
Reprodução , Transdução de Sinais , Feminino , Animais , Masculino , Reprodução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Humanos , Microplásticos/toxicidade , Nanopartículas/toxicidade
15.
Chemosphere ; 358: 142086, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38670510

RESUMO

Furan is generated in a wide array of heat-treated foods through thermal degradation, leading to severe impairments in the male reproductive system. The main objective of this study was to investigate the potential of pomegranate peel extract (PGPE) in mitigating testicular dysfunctions induced by furan. Male rats were categorized into four groups: control/untreated, PGPE, furan, and PGPE + furan group. The study results revealed that furan-treated rats exhibited significantly elevated aminotransferase and phosphatase activity, and also generated increased oxidative stress, and reduced antioxidative stress protein activity. Additionally, protein content levels (ALT, AST, ALP, and ACP) and activities of steroidogenic Leydig cell hydroxysteroid dehydrogenase (3ß-HSD and 17ß-HSD) enzymes were significantly decreased. Significant variations in testicular parameters, apoptotic genes (Bcl-2, P53, and Caspase3), inflammatory and anti-inflammatory cytokines (IL1ß, IL10), male sex hormones follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sperm quality were also observed. Furthermore, testicular histological abnormalities were confirmed by biochemical and molecular modifications. Notably, PGPE pre-treated furan-intoxicated animals exhibited significant improvements in most of the assessed parameters compared to furan-treated groups. In conclusion, PGPE presents essential preventive measures and a novel pharmacological potential therapy against furan-induced testicular injury.


Assuntos
Apoptose , Furanos , Estresse Oxidativo , Extratos Vegetais , Punica granatum , Testículo , Masculino , Animais , Estresse Oxidativo/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Ratos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Apoptose/efeitos dos fármacos , Punica granatum/química , Furanos/farmacologia , Testosterona/metabolismo , Hormônio Luteinizante , 17-Hidroxiesteroide Desidrogenases/metabolismo , Hormônio Foliculoestimulante , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Antioxidantes/metabolismo
16.
J Hazard Mater ; 465: 133151, 2024 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-38113736

RESUMO

Cadmium (Cd) is an important environmental pollutant. Herein, we discovered a new way of lipid accumulation, where lipid droplets can be transferred across cells. In this study, mice and AML12 cells were used to establish models of Cd poisoning. After Cd treatment, the level of TFAM was reduced, thereby regulating the reconstitution of the cytosolic actin filament network. MYH9 is a myosin involved in cell polarization, migration, and movement of helper organelles. Rab18 is a member of the Rab GTPase family, which localizes to lipid droplets and regulates lipid drop dynamics. In this study, we found that Cd increases the interaction between MYH9 and Rab18. However, TFAM overexpression alleviated the increase in Cd-induced interaction between MYH9 and Rab18, thereby reducing the transfer of intercellular lipid droplets and the accumulation of intracellular lipids. Through a co-culture system, we found that the transferred lipid droplets can act as a signal to form an inflammatory storm-like effect, and ACSL4 can act as an effector to transfer lipid droplets and promote lipid accumulation in surrounding cells. These results suggest that TFAM can be used as a new therapeutic target for Cd-induced lipid accumulation in the liver.


Assuntos
Cádmio , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Cádmio/metabolismo , Gotículas Lipídicas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Lipídeos , Metabolismo dos Lipídeos , Fígado/metabolismo
17.
Microbes Infect ; 26(3): 105284, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38145750

RESUMO

The increasing prevalence of drug-resistant Tuberculosis (TB) is imposing extreme difficulties in controlling the TB infection rate globally, making treatment critically challenging. To combat the prevailing situation, it is crucial to explore new anti-TB drugs with a novel mechanism of action and high efficacy. The Mycobacterium tuberculosis (M.tb)DciA is an essential protein involved in bacterial replication and regulates its growth. DciA interacts with DNA and provides critical help in binding other replication machinery proteins to the DNA. Moreover, the lack of any structural homology of M.tb DciA with human proteins makes it an appropriate target for drug development. In this study, FDA-approved drugs were virtually screened against M.tb DciA to identify potential inhibitors. Four drugs namely Lanreotide, Risedronate, Triflusal, and Zoledronic acid showed higher molecular docking scores. Further, molecular dynamics simulations analysis of DciA-drugs complexes reported stable interaction, more compactness, and reduced atomic motion. The anti-TB activity of drugs was further evaluated under in vitro and ex vivo conditions where Triflusal was observed to have the best possible activity with the MIC of 25 µg/ml. Our findings present novel DciA inhibitors and anti-TB activity of Triflusal. Further investigations on the use of Triflusal may lead to the discovery of a new anti-TB drug.


Assuntos
Mycobacterium tuberculosis , Salicilatos , Tuberculose , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Simulação de Acoplamento Molecular , Tuberculose/microbiologia , DNA/uso terapêutico
18.
Poult Sci ; 103(7): 103817, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38759568

RESUMO

Cadmium (Cd) is a common environmental pollutant associated with an increased incidence of renal metabolic diseases. Luteolin (Lut), a natural flavonoid, is widely used for its multifaceted therapeutic properties in inflammatory diseases. However, whether Lut protects against Cd-induced nephrotoxicity is still equivocal. The present study investigated the effects of Lut supplementation on renal oxidative stress, inflammation and metabolism and their related mechanisms. Therefore, 40 chickens were treated with Cd and/or Lut with automatic water and free food intake for 1 mo and then the kidney tissues were collected to explore this issue. In this study, Cd exposure induced renal glycolipid metabolism disorders and resultant kidney damage by periodic acid Schiff (PAS) staining, Oil Red O staining, total cholesterol (TC), triglyceride (TG), and glucose (Glu) levels in kidney, which were significantly ameliorated by Lut. Moreover, Lut also normalized the expression levels of factors related to Cd-disturbed glycolipid metabolism, improving metabolic homeostasis, and contributing to alleviating kidney damage. Furthermore, Lut demonstrated therapeutic potential against Cd-induced renal oxidative stress and inflammation by enhancing antioxidant capacity and inhibiting cytokine production in the kidney tissues. Mechanistically, Lut activated the AMPK/SIRT1/FOXO1 signaling pathway, attenuating oxidative stress and inflammatory responses, ameliorating the metabolic disturbance. In conclusion, these observations demonstrate that Lut treatment activates AMPK/SIRT1/FOXO1 signaling pathway, decreases oxidative stress and inflammation response, which may contribute to prevent Cd-induced metabolism disorder and consequent kidney damage.


Assuntos
Anti-Inflamatórios , Antioxidantes , Cádmio , Galinhas , Rim , Luteolina , Animais , Cádmio/toxicidade , Antioxidantes/farmacologia , Luteolina/farmacologia , Luteolina/administração & dosagem , Rim/efeitos dos fármacos , Rim/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Doenças das Aves Domésticas/induzido quimicamente , Doenças das Aves Domésticas/tratamento farmacológico , Doenças das Aves Domésticas/prevenção & controle , Inflamação/veterinária , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Nefropatias/veterinária , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Nefropatias/tratamento farmacológico , Doenças Metabólicas/veterinária , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/induzido quimicamente , Dieta/veterinária , Masculino , Suplementos Nutricionais/análise , Ração Animal/análise , Distribuição Aleatória
19.
J Biomol Struct Dyn ; : 1-15, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38321949

RESUMO

Toxin-antitoxin (TA) modules, initially discovered on bacterial plasmids and subsequently identified within chromosomal contexts, hold a pivotal role in the realm of bacterial physiology. Among these, the pioneering TA system, ccd (Control of Cell Death), primarily localized on the F-plasmid, is known for its orchestration of plasmid replication with cellular division. Nonetheless, the precise functions of such systems within bacterial chromosomal settings remain a compelling subject that demands deeper investigation. To bridge this knowledge gap, our study focuses on exploring ccdABXn2, a chromosomally encoded TA module originating from the entomopathogenic bacterium Xenorhabdus nematophila. We meticulously delved into the system's genomic assignments, structural attributes, and functional interplay. Our findings uncovered intriguing patterns-CcdB toxin homologs exhibited higher conservation levels compared to their CcdA antitoxin counterparts. Moreover, we constructed secondary as well as tertiary models for both the CcdB toxin and CcdA antitoxin using threading techniques and subsequently validated their structural integrity. Our exploration extended to the identification of key interactions, including the peptide interaction with gyrase for the CcdB homolog and CcdB toxin interactions for the CcdA homolog, highlighting the intricate TA interaction network. Through docking and simulation analyses, we unequivocally demonstrated the inhibition of replication via binding the CcdB toxin to its target, DNA gyrase. These insights provide valuable knowledge about the metabolic and physiological roles of the chromosomally encoded ccdABXn2 TA module within the context of X. nematophila, significantly enhancing our comprehension of its functional significance within the intricate ecosystem of the bacterial host.Communicated by Ramaswamy H. Sarma.

20.
Phytomedicine ; 125: 155337, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38241915

RESUMO

(Background): Cadmium is an environmental pollutant associated with several liver diseases. Baicalin and N-Acetylcysteine have antioxidant and hepatoprotective effects. (Purpose): However, it is unclear whether baicalin and N-Acetylcysteine can alleviate Cadmium -induced liver fibrosis by regulating metabolism, or whether they exert a synergistic effect. (Study design): We treated Cadmium-poisoned mice with baicalin, N-Acetylcysteine, or baicalin+ N-Acetylcysteine. We studied the effects of baicalin and N-Acetylcysteine on Cadmium-induced liver fibers and their specific mechanisms. (Methods): We used C57BL/6 J mice, and AML12, and HSC-6T cells to establish in vitro assays and in vivo models. (Results): Metabolomics was used to detect the effect of baicalin and N-Acetylcysteine on liver metabolism, which showed that compared with the control group, the Cadmium group had increased fatty acid and amino acid levels, with significantly reduced choline and acetylcholine contents. Baicalin and N-Acetylcysteine alleviated these Cadmium-induced metabolic changes. We further showed that choline alleviated Cadmium -induced liver inflammation and fibrosis. In addition, cadmium significantly promoted extracellular leakage of lactic acid, while choline alleviated the cadmium -induced destruction of the cell membrane structure and lactic acid leakage. Western blotting showed that cadmium significantly reduced mitochondrial transcription factor A (TFAM) and Choline Kinase α(CHKα2) levels, and baicalin and N-Acetylcysteine reversed this effect. Overexpression of Tfam in mouse liver and AML12 cells increased the expression of CHKα2 and the choline content, alleviating and cadmium-induced lactic acid leakage, liver inflammation, and fibrosis. (Conclusion): Overall, baicalin and N-Acetylcysteine alleviated cadmium-induced liver damage, inflammation, and fibrosis to a greater extent than either drug alone. TFAM represents a target for baicalin and N-Acetylcysteine, and alleviated cadmium-induced liver inflammation and fibrosis by regulating hepatic choline metabolism.


Assuntos
Acetilcisteína , Cádmio , Flavonoides , Camundongos , Animais , Acetilcisteína/farmacologia , Cádmio/toxicidade , Camundongos Endogâmicos C57BL , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Fígado , Inflamação/metabolismo , Colina/metabolismo , Colina/farmacologia , Colina/uso terapêutico , Ácido Láctico/metabolismo , Ácido Láctico/farmacologia , Ácido Láctico/uso terapêutico
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