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1.
J Biochem Mol Toxicol ; : e22897, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34448514

RESUMO

Phosphine (PH3 ) is widely used as an insecticide and rodenticide. On the contrary, many cases of PH3 poisoning have been reported worldwide. Unfortunately, there is no specific antidote against PH3 toxicity. Disruption of mitochondrial function and energy metabolism is a well-known mechanism of PH3 cytotoxicity. Dihydroxyacetone (DHA) is an adenosine triphosphate supplying agent which significantly improves mitochondrial function. The current study was designed to evaluate DHA's effect on inhalational PH3 poisoning in an animal model. DHA was injected into BALB/c mice before and/or after the start of the PH3 inhalation. The cytochrome c oxidase activity was assessed in the animals' brain, heart, and liver exposed to PH3 (for 15, 30, and 60 min, with and without the antidote). The LC50 of PH3 was calculated to be 18.02 (15.42-20.55) ppm over 2 h of exposure. Pretreatment of DHA (1 or 2 g/kg) increased the LC50 of PH3 by about 1.6- or 3-fold, respectively. Posttreatment with DHA (2 g/kg) increased the LC50 of PH3 by about 1.4-fold. PH3 inhibited the activity of cytochrome c oxidase in the assessed organs. It was found that DHA treatment restored mitochondrial cytochrome c oxidase activity. These findings suggested that DHA could be an effective antidote for PH3 poisoning.

2.
Biol Trace Elem Res ; 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34392478

RESUMO

The possibility of employing FeOOH nano-ellipsoids as a novel shape nano-based iron supplement was investigated. Ferrous sulfate and nano-ellipsoids were daily administered by gavage at low and high dosages. After 1 month of treatment, the hematologic parameters along with serum and organs' iron contents were measured. Liver enzymes, total serum bilirubin, and LDH level were assayed to evaluate any possible toxicity. More investigation was also performed by organ index calculation and also pathologic studies. It was found that nano-ellipsoids are an effective iron supplement to improve iron-related blood parameters. Interestingly, low-dose nano-ellipsoids were even more effective than high-dose ferrous sulfate. Nano-ellipsoids had no considerable impact on the liver enzymes and serum bilirubin. Meanwhile, high-dose ferrous sulfate significantly increases liver enzyme activity. The increased serum LDH was also the only concern in the groups that were treated with high-dose ferrous sulfate and nano-ellipsoids. Pathologic evaluations revealed some signs of liver inflammation after supplementation with high dose nano-ellipsoids and also ferrous sulfate. Overall, these data indicate FeOOH nano-ellipsoids as a novel shape iron supplement to be employed at low dosage but with greater beneficial effects than high-dose ferrous sulfate.

3.
J Control Release ; 337: 1-13, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34271033

RESUMO

Renal ischemia/reperfusion (I/R) injury is responsible for significant mortality and morbidity during renal procedures. Nitric oxide (NO) deficiency is known to play a crucial role in renal I/R injury; however, low stability and severe toxicity of high concentrations of NO have limited its applications. Herein, we developed an in-situ forming Fmoc-dipheylalanine hydrogel releasing s-nitroso-n-acetylpenicillamine (FmocFF-SNAP) for renal I/R injury. Fmoc-FF hydrogel comprising of ß-sheet nanofibers was prepared through the pH-titration method. It was then characterized by electron microscopy, pyrene assay, and circular dichroism techniques. Mechanical properties of Fmoc-FF hydrogel (thixotropy and syringeability) were investigated by oscillatory rheology and texture analysis. To assess the therapeutic efficiency in the renal I/R injury model, expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) was measured in various samples (different concentrations of free SNAP and FmocFF-SNAP, unloaded Fmoc-FF, and sham control) by real-time RT-PCR, ROS production, serum biomarkers, and histopathological evaluations. According to the results, Fmoc-FF self-assembly in physiologic conditions led to the formation of an entangled nanofibrous and shear-thinning hydrogel. FmocFF-SNAP exhibited a sustained NO release over 7 days in a concentration-dependent manner. Importantly, intralesional injection of FmocFF-SNAP caused superior recovery of renal I/R injury when compared to free SNAP in terms of histopathological scores and renal function indices (e.g. serum creatinine, and blood urea nitrogen). Compared to the I/R control group, biomarkers of oxidative stress and iNOS expression were significantly reduced possibly due to the sustained release of NO. Interestingly, the eNOS expression showed a significant enhancement reflecting the regeneration of the injured endothelial tissue. Thus, the novel FmocFF-SNAP can be recommended for the alleviation of renal I/R injury.

4.
Biomed Res Int ; 2021: 5526644, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34212031

RESUMO

Wallflower (Erysimum cheiri) is employed as a popular herbal drug in traditional Persian medicine. Topical formulations including cerates, lotions, sitz baths, and poultices for inflammatory disorders such as arthritis, anal fissure, endometriosis, and mastitis are known. However, there is no monograph in current pharmacopoeia for the wallflower drug. The present study is aimed to screen in vitro anti-inflammatory activity of wallflower and perform quality control and characterization tests for different organs of the herb. In this regard, albumin denaturation activity, macroscopic and microscopic, phytochemical, HPTLC, and FT-IR characteristics were investigated. Wallflower showed strong anti-inflammatory activity compared to diclofenac sodium. The root (1.25, 2.5, and 5 mg/mL) and flower (10 mg/mL) extract exhibited higher anti-inflammatory activities than that of other plant organs at the same concentrations. Moreover, total ash was found higher in aerial parts (21.52 ± 0.06%) than flower (11.01 ± 0.03%), root (5.03 ± 0.03%), and seed (6.95 ± 0.06%), while water-soluble ash was higher in seed (34.89 ± 0.26%) than flower (5.00 ± 0.03%), aerial parts (7.16 ± 0.06%), and root (5.04 ± 0.01%). Acid-insoluble ash and sulphated ash were higher in root (9.50 ± 0.04%) and aerial part (28.37 ± 0.57%), respectively. In addition, loss on drying was ranged from 2.20 ± 0.20% in flowers to 6.00 ± 0.10% in aerial parts. On the other hand, HPTLC analysis verified cardenolide compounds in all organs of the herb, and quercetin was detected in the flavonoid fingerprint of acid hydrolysed flowers. According to FT-IR results, the observed spectral region at ~3500 cm-1 attributed to -OH stretching vibration. Also, C-H (~2900-2950 cm-1), isothiocyanate (~2340 cm-1), -C=O (~1740 cm-1), conjugated C=C of the aromatic ring (~1650 cm-1), and structure of the aromatic group (~1200-1000 cm-1) were monitored. This work is the first study to the best of our knowledge, suggesting wallflower as a potential drug candidate with the basis for a monograph in addition to initial in vitro anti-inflammatory data.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Erysimum/química , Flavonoides/química , Flavonoides/farmacologia , Flores/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Controle de Qualidade , Quercetina/química , Quercetina/farmacologia , Sementes/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos
5.
J Biochem Mol Toxicol ; 35(9): e22846, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34250697

RESUMO

The liver is the primary organ affected by cholestasis. However, the brain, skeletal muscle, heart, and kidney are also severely influenced by cholestasis/cirrhosis. However, little is known about the molecular mechanisms of organ injury in cholestasis. The current study was designed to evaluate the mitochondrial glutathione redox state as a significant index in cell death. Moreover, tissue energy charge (EC) was calculated. Rats underwent bile duct ligation (BDL) and the brain, heart, liver, kidney, and skeletal muscle mitochondria were assessed at scheduled time intervals (3, 7, 14, and 28 days after BDL). A significant decrease in mitochondrial glutathione redox state and EC was detected in BDL animals. Moreover, disturbed mitochondrial indices were evident in different organs of BDL rats. These data could offer new insight into the mechanisms of organ injury and the source of oxidative stress during cholestasis and might provide novel therapeutic strategies against these complications.


Assuntos
Colestase/metabolismo , Metabolismo Energético , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Musculares/metabolismo , Animais , Colestase/patologia , Modelos Animais de Doenças , Masculino , Mitocôndrias Hepáticas/patologia , Mitocôndrias Musculares/patologia , Especificidade de Órgãos , Oxirredução , Ratos , Ratos Sprague-Dawley
6.
Mutat Res Rev Mutat Res ; 787: 108375, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083033

RESUMO

The human transcriptome contains many non-coding RNAs (ncRNAs), which play important roles in gene regulation. Long noncoding RNAs (lncRNAs) are an important class of ncRNAs with lengths between 200 and 200,000 bases. Unlike mRNA, lncRNA lacks protein-coding features, specifically, open-reading frames, and start and stop codons. LncRNAs have been reported to play a role in the pathogenesis and progression of many cancers, including breast cancer (BC), acting as tumor suppressors or oncogenes. In this review, we systematically mined the literature to identify 65 BC-related lncRNAs. We then perform an integrative bioinformatics analysis to identify 14 lncRNAs with a potential regulatory role in BC. The biological function of these 14 lncRNAs, their regulatory mechanisms, and roles in the initiation and progression of BC are discussed in this review. Additionally, we elaborate on the current and future applications of lncRNAs as diagnostic and/or therapeutic biomarkers in BC.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , RNA Longo não Codificante/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos
7.
Toxicol Lett ; 349: 12-29, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089816

RESUMO

The cholestatic liver injury could occur in response to a variety of diseases or xenobiotics. Although cholestasis primarily affects liver function, it has been well-known that other organs such as the kidney could be influenced in cholestatic patients. Severe cholestasis could lead to tissue fibrosis and organ failure. Unfortunately, there is no specific therapeutic option against cholestasis-induced organ injury. Hence, finding the mechanism of organ injury during cholestasis could lead to therapeutic options against this complication. The accumulation of potentially cytotoxic compounds such as hydrophobic bile acids is the most suspected mechanism involved in the pathogenesis of cholestasis-induced organ injury. A plethora of evidence indicates a role for the inflammatory response in the pathogenesis of several human diseases. Here, the role of nuclear factor-kB (NFkB)-mediated inflammatory response is investigated in an animal model of cholestasis. Bile duct ligated (BDL) animals were treated with sulfasalazine (SSLZ, 10 and 100 mg/kg, i.p) as a potent inhibitor of NFkB signaling. The NFkB proteins family activity in the liver and kidney, serum and tissue levels of pro-inflammatory cytokines, tissue biomarkers of oxidative stress, serum markers of organ injury, and the liver and kidney histopathological alterations and fibrotic changes. The oxidative stress-mediated inflammatory-related indices were monitored in the kidney and liver at scheduled time intervals (3, 7, and 14 days after BDL operation). Significant increase in serum and urine markers of organ injury, besides changes in biomarkers of oxidative stress and tissue histopathology, were evident in the liver and kidney of BDL animals. The activity of NFkB proteins (p65, p50, p52, c-Rel, and RelB) was significantly increased in the liver and kidney of cholestatic animals. Serum and tissue levels of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-7, IL-12, IL-17, IL-18, IL-23, TNF-α, and INF-γ) were also higher than sham-operated animals. Moreover, TGF- ß, α-SMA, and tissue fibrosis (Trichrome stain) were evident in cholestatic animals' liver and kidneys. It was found that SSLZ (10 and 100 mg/kg/day, i.p) alleviated cholestasis-induced hepatic and renal injury. The effect of SSLZ on NFkB signaling and suppression of pro-inflammatory cytokines could play a significant role in its protective role in cholestasis. Based on these data, NFkB signaling could receive special attention to develop therapeutic options to blunt cholestasis-induced organ injury.


Assuntos
Anti-Inflamatórios/farmacologia , Colestase/tratamento farmacológico , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sulfassalazina/farmacologia , Animais , Colestase/metabolismo , Colestase/patologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Regulação para Baixo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
8.
Int J Pharm ; 602: 120685, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33964340

RESUMO

The surfactant template-directed solvothermal method was applied in the synthesis of hierarchical mesoporous zinc-imidazolate derivative metal-organic framework (mesoMOF), which was then utilized for active loading of cisplatin (cis-Pt). To fabricate mesoMOF, various amounts of the surfactant (cetyltrimethylammonium bromide: 0.1-0.3 g) and linker (citric acid: 0.05-0.15 g) were added to the reaction mixture, which resulted in different particle sizes and morphologies. MesoMOF quality attributes such as Specific surface area (SSA), total porous volume, and Barrett-Joyner-Halenda (BJH) pore diameter were also determined. At the optimum reaction condition, mesoMOF with a high surface area (1859 m2/g), pore diameter (14.13 nm) and total pore volume (0.314 cm3/g) was attained. In the next step, cis-Pt was actively loaded in the mesoMOF with a high loading capacity (28% w/w), which was remarkably superior to the microporous MOF. Interestingly, in mildly acidic pH (5.5), mesoMOF underwent degradation, resulting in a rapid release of cis-Pt. Cell viability and apoptosis induction assays confirmed the superiority of the cis-Pt loaded mesoMOF over free drug in a resistant ovarian tumor cell line (A2780cp). Altogether, due to their tunable size and morphology, pH-responsiveness, and acceptable tolerability in mice, the mesoMOFs can be regarded as an anti-cancer drug delivery system.


Assuntos
Preparações Farmacêuticas , Zinco , Animais , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Imidazóis , Camundongos , Tensoativos
9.
J Biochem Mol Toxicol ; 35(7): e22795, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33973313

RESUMO

The world is currently facing an unprecedented pandemic caused by a newly recognized and highly pathogenic coronavirus disease 2019 (COVID-19; induced by SARS-CoV-2 virus), which is a severe and ongoing threat to global public health. Since COVID-19 was officially declared a pandemic by the World Health Organization in March 2020, several drug regimens have rapidly undergone clinical trials for the management of COVID-19. However, one of the major issues is drug-induced organ injury, which is a prominent clinical challenge. Unfortunately, most drugs used against COVID-19 are associated with adverse effects in different organs, such as the kidney, heart, and liver. These side effects are dangerous and, in some cases, they can be lethal. More importantly, organ injury is also a clinical manifestation of COVID-19 infection. These adverse reactions are increasingly recognized as outcomes of COVID-19 infection. Therefore, the differential diagnosis of drug-induced adverse effects from COVID-19-induced organ injury is a clinical complication. This review highlights the importance of drug-induced organ injury, its known mechanisms, and the potential therapeutic strategies in COVID-19 pharmacotherapy. We review the potential strategies for the differential diagnosis of drug-induced organ injury. This information can facilitate the development of therapeutic strategies, not only against COVID-19 but also for future outbreaks of other emerging infectious diseases.


Assuntos
Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , Biomarcadores/análise , COVID-19/metabolismo , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/lesões , Diagnóstico Diferencial , Humanos , Inflamação , Rim/efeitos dos fármacos , Rim/lesões , Fígado/efeitos dos fármacos , Fígado/lesões , Estresse Oxidativo
11.
Naunyn Schmiedebergs Arch Pharmacol ; 394(6): 1191-1203, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33527194

RESUMO

Cholestasis is a clinical complication with different etiologies. The liver is the primary organ influenced in cholestasis. Renal injury is also a severe clinical complication in cholestatic/cirrhotic patients. Several studies mentioned the importance of oxidative stress and mitochondrial impairment as two mechanistically interrelated events in cholestasis-induced organ injury. Apoptosis-inducing factor (AIF) is a flavoprotein located in the inner mitochondrial membrane. This molecule is involved in a distinct pathway of cell death. The current study aimed to evaluate the role of AIF in the pathophysiology of cholestasis-associated hepatic and renal injury. Bile duct ligation (BDL) was used as an animal model of cholestasis. Serum, urine, and tissue samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Tissues' AIF mRNA levels, as well as serum, urine, and tissue activity of AIF, were measured. Moreover, markers of DNA fragmentation and apoptosis were assessed in the liver and kidney of cholestatic animals. A significant increase in liver and kidney AIF mRNA levels, in addition to increased AIF activity in the liver, kidney, serum, and urine, was detected in BDL rats. DNA fragmentation and apoptosis were raised in the liver and kidney of cholestatic animals, especially at the early stage of the disease. The apoptotic mode of cell death in the liver and kidney was connected to a higher AIF level. These data mention the importance of AIF in the pathogenesis of cholestasis-induced organ injury, especially at the early stage of this disease. Mitochondrial release of apoptosis-inducing factor (AIF) seems to play a pathogenic role in cholestasis-associated hepatic and renal injury. AIF release is directly connected to oxidative stress and mitochondrial impairment in cholestatic animals.

12.
Naunyn Schmiedebergs Arch Pharmacol ; 394(6): 1301-1314, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33538845

RESUMO

Bile duct obstruction or cholestasis can occur by several diseases or xenobiotics. Cholestasis and the accumulation of the bile constituents in the liver primarily damage this organ. On the other hand, extrahepatic organs are also affected by cholestasis. The kidney is the most affected tissue during cholestatic liver injury. Cholestasis-associated renal injury is known as cholemic nephropathy (CN). Several lines of evidence specify the involvement of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to assess the role of silymarin as a potent antioxidant on CN-induced oxidative stress and mitochondrial dysfunction in the kidney. Bile duct ligated (BDL) rats were treated with silymarin (10 and 100 mg/kg, oral) for seven consecutive days. A significant increase in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and oxidized glutathione (GSSG) levels were evident in the kidney of BDL animals. Moreover, reduced glutathione (GSH) content and total antioxidant capacity were significantly decreased in the kidney of cholestatic rats. Mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and depleted ATP stores were detected in the kidney mitochondria isolated from BDL animals. Kidney histopathological alterations, as well as serum and urine levels of renal injury biomarkers, were also significantly different in the BDL group. It was found that silymarin treatment significantly ameliorated CN-induced renal injury. The antioxidant effects of silymarin and its positive impact on mitochondrial indices seem to play a significant role in its renoprotective effects during cholestasis.

13.
CNS Neurosci Ther ; 27(3): 308-319, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33497031

RESUMO

AIMS: Experimental and clinical evidences demonstrate that common dysregulated pathways are involved in Parkinson's disease (PD) and type 2 diabetes. Recently, insulin treatment through intranasal (IN) approach has gained attention in PD, although the underlying mechanism of its potential therapeutic effects is still unclear. In this study, we investigated the effects of insulin treatment in a rat model of PD with emphasis on mitochondrial function indices in striatum. METHODS: Rats were treated with a daily low dose (4IU/day) of IN insulin, starting 72 h after 6-OHDA-induced lesion and continued for 14 days. Motor performance, dopaminergic cell survival, mitochondrial dehydrogenases activity, mitochondrial swelling, mitochondria permeability transition pore (mPTP), mitochondrial membrane potential (Δψm ), reactive oxygen species (ROS) formation, and glutathione (GSH) content in mitochondria, mitochondrial adenosine triphosphate (ATP), and the gene expression of PGC-1α, TFAM, Drp-1, GFAP, and Iba-1 were assessed. RESULTS: Intranasal insulin significantly reduces 6-OHDA-induced motor dysfunction and dopaminergic cell death. In parallel, it improves mitochondrial function indices and modulates mitochondria biogenesis and fission as well as activation of astrocytes and microglia. CONCLUSION: Considering the prominent role of mitochondrial dysfunction in PD pathology, IN insulin as a disease-modifying therapy for PD should be considered for extensive research.

14.
Curr Pharm Biotechnol ; 22(14): 1900-1909, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33390108

RESUMO

BACKGROUND: Streptococcus pneumoniae is the leading cause of pneumonia, mostly in children less than five years and elderly people. Although the Pneumoniae Polysaccharide Vaccine (PPV) and Pneumonia Conjugate Vaccines (PCV) are the efficient pneumococcal vaccine in adults and children, the serotype replacement of S. pneumoniae strains causes the reduction in the efficacy of PPV and PCV vaccines. Epitope-based vaccines are a promising alternative to the present capsular antigen vaccines. METHODS: In this study, we evaluated cellular and humoral immune responses induced by our novel designed multi-epitope vaccine in BALB/c mice. CD8+ Cytolytic T Lymphocytes (CTLs) epitopes were selected from PspA and CbpA antigens, and CD4+ Helper T Lymphocytes (HTLs) epitopes were chosen from PhtD and PiuA antigens. PorB, the TLR2 agonist, as an adjuvant, was employed to increase the immunogenicity of the vaccine. RESULTS AND CONCLUSION: The high levels of specific anti-peptide vaccine IgG and an increase in the level of IgG2 in the vaccinated group demonstrated our vaccine could elicit robust antibody production. The significant increase in IFN-γ, IL-2, TNF-α, IL-4, IL-6, and decrease in IL-10 showed that the designed vaccine could be proposed as the efficient preventative pneumococcal vaccine in the mouse model.


Assuntos
Epitopos Imunodominantes , Vacinas Pneumocócicas , Animais , Proteínas de Bactérias , Epitopos de Linfócito T , Camundongos , Camundongos Endogâmicos BALB C
15.
Biol Trace Elem Res ; 199(5): 1908-1918, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32712907

RESUMO

Lithium is abundantly administered against bipolar disorder. On the other hand, the lithium-induced renal injury is a clinical complication which commonly reveals as drug-induced diabetes insipidus. However, lithium-induced cytotoxicity might also play a role in the adverse effects of this drug on the kidney. There is no clear cellular and molecular mechanism(s) for lithium-induced nephrotoxicity. The current study was designed to assess the effect of lithium on kidney tissue oxidative stress biomarkers and mitochondrial function and its relevance to drug-induced nephrotoxicity and electrolyte imbalance. Rats were treated with lithium (lithium carbonate, 25 and 50 mg/kg/day, i.p., for 28 consecutive days). Kidney mitochondria were also isolated from rats and exposed to increasing concentrations of lithium (0.01-10 mM). Serum and urine biomarkers of kidney injury, kidney tissue markers of oxidative stress, and renal histopathological changes were assessed. Moreover, several mitochondrial indices were monitored. Lithium-induced renal injury revealed a significant increase in urine and serum biomarkers of renal impairment. Lithium caused an increase in the kidney reactive oxygen species (ROS) level and lipid peroxidation (LPO). Renal glutathione (GSH) reservoirs were also depleted, and tissue antioxidant capacity decreased in lithium-treated animals. Significant tissue histopathological changes, including necrosis, Bowman capsule dilation, and interstitial inflammation, were evident in lithium-treated animals. On the other hand, significant alterations in kidney mitochondrial function were detected in lithium-treated groups. These data mention oxidative stress, mitochondrial dysfunction, and cellular energy crisis as the potential primary mechanisms for lithium-induced renal injury.


Assuntos
Lítio , Mitocôndrias , Animais , Antioxidantes/metabolismo , Rim/metabolismo , Peroxidação de Lipídeos , Lítio/toxicidade , Mitocôndrias/metabolismo , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio/metabolismo
16.
Stress ; 24(2): 213-228, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32510264

RESUMO

Cholestasis is a multifaceted clinical complication. Obstructive jaundice induced by bile duct ligation (BDL) is known as an animal model to investigate cholestasis and its associated complications. N-acetyl cysteine (NAC) is an antioxidant, radical scavenger, and thiol reductant widely investigated for its cytoprotective properties. The current investigation was designed to evaluate the role of NAC treatment on biomarkers of oxidative stress and organ histopathological alterations in a rat model of cholestasis/cirrhosis. BDL animals were supplemented with NAC (100 and 300 mg/kg, i.p, 42 consecutive days). Biomarkers of oxidative stress in the liver, brain, heart, skeletal muscle, lung, serum, and kidney tissue, as well as organ histopathological changes, were monitored. A significant increase in reactive oxygen species, lipid peroxidation, and protein carbonylation were detected in different tissues of BDL rats. Moreover, tissue antioxidant capacity was hampered, glutathione (GSH) reservoirs were depleted, and oxidized glutathione (GSSG) levels were significantly increased in the BDL group. Significant tissue histopathological alterations were evident in cirrhotic animals. It was found that NAC treatment (100 and 300 mg/kg, i.p) significantly mitigated biomarkers of oxidative stress and alleviated tissue histopathological changes in cirrhotic rats. These data represent NAC as a potential protective agent with therapeutic capability in cirrhosis and its associated complications.HIGHLIGHTSCholestasis is a multifaceted clinical complication that affects different organsOxidative stress plays a pivotal role in cholestasis-associated complicationsTissue antioxidant capacity is hampered in different tissues of cholestatic animalsAntioxidant therapy might play a role in the management of cholestasis-induced organ injuryNAC alleviated biomarkers of oxidative stress in cholestatic animalsNAC significantly improved tissues histopathological alterations in cholestatic rats.


Assuntos
Acetilcisteína , Estresse Psicológico , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Animais , Ductos Biliares/metabolismo , Ductos Biliares/cirurgia , Biomarcadores/metabolismo , Fígado/metabolismo , Estresse Oxidativo , Ratos
17.
Int J Nanomedicine ; 15: 10085-10098, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363368

RESUMO

Purpose: Hepatic encephalopathy (HE) is a critical situation in which liver failure affects brain function. HE could result in a state of coma and death. The liver is the main organ for ammonium ion (NH4 +) metabolism. Hence, acute and/or chronic liver failure could lead to hyperammonemia. NH4 + is the most suspected neurotoxic agent in HE. Thus, finding new therapeutic options to decrease plasma and brain NH4 + levels has a significant clinical value. Mesoporous silica (MS) particles have revolutionized many aspects of pharmaceutical sciences, including drug delivery systems. Moreover, recently, MS has been applied as agents for the detoxification of chemicals (eg, drugs and poisons). Methods: First, MS particles containing amine groups (MS-NH2) were synthesized in co-condensation processes. Then, the structure was modified by succinic anhydride to have MS-SA. The MS-SA was characterized (FT-IR, XRD, X-ray photoelectron spectroscopy (XPS), DLS-Zeta FESEM-EDX, and HRTEM). Then, the potential of MS-NH2 and MS-SA particles in adsorption of NH4 + was investigated in vitro and in vivo. MS-NH2 and MS-SA were incubated with increasing concentrations (0.1-10 mM) of NH4 +, and the scavenging capacity of the investigated particles was evaluated. On the other hand, different doses (1 and 5 mg/kg per day) of nanoparticles were administered to a hyperammonemia animal model. Results: It was figured out that both MS-NH2 and MS-SA significantly scavenged NH4 + in the in vitro model. However, the NH4 + scavenging capability of MS-SA was more significant. Administration of MS-NH2 and MS-SA also considerably decreased the level of ammonium in plasma and brain and improved cognitive and locomotor activity in hyperammonemic animals. The effects of MS-SA were more significant than MS-NH2 in the HE animal model. Conclusion: Collectively, our data suggest that MS particles, especially succinic acid-functionalized MS, could act as special ancillary treatment in HE as a critical clinical complication.


Assuntos
Amônia/isolamento & purificação , Encefalopatia Hepática/terapia , Dióxido de Silício/química , Ácido Succínico/química , Adsorção , Animais , Biomarcadores/sangue , Encéfalo/metabolismo , Modelos Animais de Doenças , Encefalopatia Hepática/sangue , Encefalopatia Hepática/fisiopatologia , Íons , Fígado/patologia , Masculino , Atividade Motora , Nanopartículas/química , Tamanho da Partícula , Espectroscopia Fotoeletrônica , Porosidade , Ratos Sprague-Dawley , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Difração de Raios X
18.
J Exp Pharmacol ; 12: 517-527, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33235522

RESUMO

Purpose: Hepatic encephalopathy (HE) is described as impaired brain function induced by liver failure. Ammonia is the most suspected chemical involved in brain injury during HE. Although the precise mechanism of HE is not clear, several studies mentioned the role of oxidative stress in ammonia neurotoxicity. In animal models, the use of some compounds with antioxidant properties was reported to reduce the neurotoxic effects of ammonia, improve energy metabolism, and ameliorate the HE symptoms. Citicoline is a principal intermediate in the biosynthesis pathway of phosphatidylcholine that acts as neurovascular protection and repair effects. Various studies mentioned the neuroprotective and antioxidative effects of citicoline in the central nervous system. This study aims to investigate the potential protective effects of citicoline therapeutic in an animal model of HE. Materials and Methods: Mice received acetaminophen (APAP,1g/kg, i. p.) and then treated with citicoline (500 mg/kg, i.p) one and two hours after APAP. Animals were monitored for locomotor activity and blood and brain ammonia levels. Moreover, markers of oxidative stress were assessed in the brain tissue. Results: The result of the study revealed that plasma and brain ammonia and the liver injury markers increased, and locomotor activity impaired in the APAP-treated animals. Besides, an increase in markers of oxidative stress was evident in the brain of the APAP-treated mice. It was found that citicoline supplementation enhanced the animal's locomotor activity and improved brain tissue markers of oxidative stress. Conclusion: These data propose citicoline as a potential protective agent in HE. The effects of citicoline on oxidative stress markers could play a fundamental role in its neuroprotective properties during HE.

19.
Clin Exp Hepatol ; 6(3): 207-219, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33145427

RESUMO

Cirrhosis-induced heart injury and cardiomyopathy is a serious consequence of this disease. It has been shown that bile duct ligated (BDL) animals could serve as an appropriate experimental model to investigate heart tissue injury in cirrhosis. The accumulation of cytotoxic chemicals (e.g., bile acids) could also adversely affect the heart tissue. Oxidative stress and mitochondrial impairment are the most prominent mechanisms of bile acid cytotoxicity. Taurine (Tau) is the most abundant non-protein amino acid in the human body. The cardioprotective effects of this amino acid have repeatedly been investigated. In the current study, it was examined whether mitochondrial dysfunction and oxidative stress are involved in the pathogenesis of cirrhosis-induced heart injury. Rats underwent BDL surgery. BDL animals received Tau (50, 100, and 500 mg/kg, i.p.) for 42 consecutive days. A significant increase in oxidative stress biomarkers was detected in the heart tissue of BDL animals. Moreover, it was found that heart tissue mitochondrial indices of functionality were deteriorated in the BDL group. Tau treatment significantly decreased oxidative stress and improved mitochondrial function in the heart tissue of cirrhotic animals. These data provide clues for the involvement of mitochondrial impairment and oxidative stress in the pathogenesis of heart injury in BDL rats. On the other hand, Tau supplementation could serve as an effective ancillary treatment against BDL-associated heart injury. Mitochondrial regulating and antioxidative properties of Tau might play a fundamental role in its mechanism of protective effects in the heart tissue of BDL animals.

20.
Int J Hematol Oncol Stem Cell Res ; 14(3): 200-212, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33024527

RESUMO

Background: Chromosomal breakpoints are the most common cause of hereditary diseases and cancers. Today, many standard clinical methods such as cytogenetic and PCR based techniques are used which have limitation regarding detection resolution. Chromosome conformation capture is a method for detecting gene proximity and chromosomal rearrangements. Materials and Methods: In this study, SKW3 cell line was used for detecting t(8;14)(q24;q11) using a 3C-based technique. SKW3 cell line was used for 3C library preparation. For Inverse PCR, two regions were selected in upstream and downstream of the viewpoint locus on chromosome 8-MYC gene based on EcoRI restriction sites. The captured sequence with intra-chromosomal interaction between chr8-c-MYC and chr14-TRD was selected for the translocation PCR primer design. Results: The DNA fragment captured in 3C PCR showed a specific TRD sequence translocated downstream of the MYC gene. Translocation PCR demonstrated the existence of (8; 14) (q24; q11) MYC /TRD in both library and genomic DNA. Conclusion: This result demonstrated 3C- based method could be used as a useful low-cost easy operating technique in chromosomal rearrangements detection. In this study, the integration of whole genome library monitoring and PCR method was used as a high- through put method in chromosomal breakpoints detection.

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