RESUMO
Nanoplastics (NPs) pollution has become a global environmental problem, raising numerous health concerns. However, the cardiotoxicity of NPs exposure and the underlying mechanisms have been understudied to date. To address this issue, we comprehensively evaluated the cardiotoxicity of polystyrene nanoplastics (PS-NPs) in both healthy and pathological states. Briefly, mice were orally exposed to four different concentrations (0 mg/day, 0.1 mg/day, 0.5 mg/day, and 2.5 mg/day) of 100-nm PS-NPs for 6 weeks to assess their cardiotoxicity in a healthy state. Considering that individuals with underlying health conditions are more vulnerable to the adverse effects of pollution, we further investigated the cardiotoxic effects of PS-NPs on pathological states induced by isoprenaline. Results showed that PS-NPs induced cardiomyocyte apoptosis, cardiac fibrosis, and myocardial dysfunction in healthy mice and exacerbated cardiac remodeling in pathological states. RNA sequencing revealed that PS-NPs significantly upregulated homeodomain interacting protein kinase 2 (HIPK2) in the heart and activated the P53 and TGF-beta signaling pathways. Pharmacological inhibition of HIPK2 reduced P53 phosphorylation and inhibited the activation of the TGF-ß1/Smad3 pathway, which in turn decreased PS-NPs-induced cardiotoxicity. This study elucidated the potential mechanisms underlying PS-NPs-induced cardiotoxicity and underscored the importance of evaluating nanoplastics safety, particularly for individuals with pre-existing heart conditions.
Assuntos
Cardiotoxicidade , Poliestirenos , Proteínas Serina-Treonina Quinases , Proteína Smad3 , Fator de Crescimento Transformador beta1 , Proteína Supressora de Tumor p53 , Regulação para Cima , Animais , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Proteína Smad3/metabolismo , Proteína Smad3/genética , Cardiotoxicidade/etiologia , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Poliestirenos/toxicidade , Regulação para Cima/efeitos dos fármacos , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Nanopartículas/toxicidade , Miocárdio/metabolismo , Miocárdio/patologiaRESUMO
BACKGROUND & AIMS: The spread of foot-and-mouth disease virus (FMDV) through aerosol droplets among cloven-hoofed ungulates in close contact is a major obstacle for successful animal husbandry. Therefore, the development of suitable mucosal vaccines, especially nasal vaccines, to block the virus at the initial site of infection is crucial. PATIENTS AND METHODS: Here, we constructed eukaryotic expression plasmids containing the T and B-cell epitopes (pTB) of FMDV in tandem with the molecular mucosal adjuvant Fms-like tyrosine kinase receptor 3 ligand (Flt3 ligand, FL) (pTB-FL). Then, the constructed plasmid was electrostatically attached to mannose-modified chitosan-coated poly(lactic-co-glycolic) acid (PLGA) nanospheres (MCS-PLGA-NPs) to obtain an active nasal vaccine targeting the mannose-receptor on the surface of antigen-presenting cells (APCs). RESULTS: The MCS-PLGA-NPs loaded with pTB-FL not only induced a local mucosal immune response, but also induced a systemic immune response in mice. More importantly, the nasal vaccine afforded an 80% protection rate against a highly virulent FMDV strain (AF72) when it was subcutaneously injected into the soles of the feet of guinea pigs. CONCLUSIONS: The nasal vaccine prepared in this study can effectively induce a cross-protective immune response against the challenge with FMDV of same serotype in animals and is promising as a potential FMDV vaccine.
Assuntos
Administração Intranasal , Quitosana , Vírus da Febre Aftosa , Febre Aftosa , Nanosferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Vacinas Virais , Animais , Quitosana/química , Quitosana/administração & dosagem , Vírus da Febre Aftosa/imunologia , Vírus da Febre Aftosa/genética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Febre Aftosa/prevenção & controle , Febre Aftosa/imunologia , Camundongos , Nanosferas/química , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Camundongos Endogâmicos BALB C , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Feminino , Ácidos Nucleicos/administração & dosagem , Imunidade nas Mucosas , Sistemas de Liberação de MedicamentosRESUMO
Methamphetamine (METH) is a psychostimulant drug belonging to the amphetamine-type stimulant class, known to exert male reproductive toxicity. Recent studies suggest that METH can disrupt the gut microbiota. Furthermore, the gut-testis axis concept has gained attention due to the potential link between gut microbiome dysfunction and reproductive health. Nonetheless, the role of the gut microbiota in mediating the impact of METH on male reproductive toxicity remains unclear. In this study, we employed a mouse model exposed to escalating doses of METH to assess sperm quality, testicular pathology, and reproductive hormone levels. The fecal microbiota transplantation method was employed to investigate the effect of gut microbiota on male reproductive toxicity. Transcriptomic, metabolomic, and microbiological analyses were conducted to explore the damage mechanism to the male reproductive system caused by METH. We found that METH exposure led to hormonal disorders, decreased sperm quality, and changes in the gut microbiota and testicular metabolome in mice. Testicular RNA sequencing revealed enrichment of several Gene Ontology terms associated with reproductive processes, as well as PI3K-Akt signaling pathways. FMT conveyed similar reproductive damage from METH-treated mice to healthy recipient mice. The aforementioned findings suggest that the gut microbiota plays a substantial role in facilitating the reproductive toxicity caused by METH, thereby highlighting a prospective avenue for therapeutic intervention in the context of METH-induced infertility.
Assuntos
Microbioma Gastrointestinal , Metanfetamina , Reprodução , Testículo , Animais , Metanfetamina/toxicidade , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Testículo/efeitos dos fármacos , Testículo/patologia , Reprodução/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Estimulantes do Sistema Nervoso Central/toxicidade , Transplante de Microbiota FecalRESUMO
Mother nature accomplishes efficient ammonia synthesis via cascade N2 oxidation by lightning strikes followed with enzyme-catalyzed nitrogen oxyanion (NOx -, x = 2,3) reduction. The protein environment of enzymatic centers for NOx --to-NH4 + process greatly inspires the design of glutathione-capped (GSH) quantum dots (QDs) for ammonia synthesis under visible light (440 nm) in tandem with plasma-enabled N2 oxidation. Mechanistic studies reveal that GSH induces positive shift of surface charge to strengthen the interaction between NOx - and QDs. Upon visible light irradiation of QDs, the balanced and rapid hole and electron transfer furnish GS·radicals for 2e-/2H+ alcohol oxidation and H·for 8e-/10H+ NO3 --to-NH4 + reduction simultaneously. For the first time, mmol-scale ammonia synthesis is realized with apparent quantum yields of 5.45% ± 0.64%, and gram-scale synthesis of value-added acetophenone and NH4Cl proceeds with 1:4 stoichiometry and stability, demonstrating promising multielectron and multiproton ammonia synthesis efficiency and sustainability with nature-inspired artificial photocatalysts.
RESUMO
Organophosphorus flame retardants (OPFRs), such as 2-ethylhexyl diphenyl phosphate (EHDPHP), are ubiquitously used, leading to pervasive environmental contamination and human health risks. While associations between EHDPHP and health issues such as disruption of hormones, neurotoxic effects, and toxicity to reproduction have been recognized, exposure to EHDPHP during perinatal life and its implications for the intestinal health of dams and their pups have largely been unexplored. This study investigated the intestinal toxicity of EHDPHP and the potential for which inulin was effective. Dams were administered either an EHDPHP solution or a corn oil control from gestation day 7 (GD7) to postnatal day 21 (PND21), with inulin provided in their drinking water. Our results indicate that inulin supplementation mitigates damage to the intestinal epithelium caused by EHDPHP, restores mucus-secreting cells, suppresses intestinal hyperpermeability, and abates intestinal inflammation by curtailing lipopolysaccharide leakage through reshaping of the gut microbiota. A reduction in LPS levels concurrently inhibited the inflammation-associated TLR4/NF-κB pathway. In conclusion, inulin administration may ameliorate intestinal toxicity caused by EHDPHP in dams and pups by reshaping the gut microbiota and suppressing the LPS/TLR4/NF-κB pathway. These findings underscore the efficacy of inulin as a therapeutic agent for managing health risks linked to EHDPHP exposure.
Assuntos
Compostos de Bifenilo , Microbioma Gastrointestinal , Fosfatos , Gravidez , Feminino , Humanos , Fosfatos/farmacologia , NF-kappa B , Lipopolissacarídeos , Inulina/farmacologia , Receptor 4 Toll-Like/metabolismo , InflamaçãoRESUMO
Inherent chirality is used to describe chiral cyclic molecules devoid of central, axial, planar, or helical chirality and has tremendous applications in chiral recognition and enantioselective synthesis. Catalytic and divergent syntheses of inherently chiral molecules have attracted increasing interest from chemists. Herein, we report the enantioselective synthesis of inherently chiral tribenzocycloheptene derivatives via chiral phosphoric acid (CPA)-catalyzed condensation of cyclic ketones and hydroxylamines. This chemistry paves the way to accessing the less stable derivatives of 7-membered rings with inherent chirality. A series of chiral tribenzocycloheptene oxime ethers was synthesized in good yields (up to 97 %) with excellent enantioselectivities (up to 99 % ee).
RESUMO
Prenatal exposure to methamphetamine (METH) is an issue of global concern due to its adverse effects on offspring, particularly its impact on liver health, an area still not fully understood. Inulin, a recognized prebiotic, is thought to potentially ameliorate these developmental disorders and toxic injuries in progeny. To investigate the effects of prenatal METH exposure on the liver and the role of gut microbiota, we established a murine model, the subjects of which were exposed to METH prenatally and subsequently treated with inulin. Our findings indicate that prenatal METH exposure causes liver damage in offspring, as evidenced by a decreased liver index, histopathological changes, diminished glycogen synthesis, hepatic dysfunction, and alterations in mRNA profiles. Furthermore, it impairs the antioxidant system and induces oxidative stress, possibly due to changes in cecal microbiota and dysregulation of bile acid homeostasis. However, maternal inulin supplementation appears to restore the gut microbiota in offspring and mitigate the hepatotoxic effects induced by prenatal METH exposure. Our study provides definitive evidence of METH's transgenerational hepatotoxicity and suggests that maternal inulin supplementation could be an effective preventive strategy.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Microbioma Gastrointestinal , Metanfetamina , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Feminino , Camundongos , Animais , Humanos , Metanfetamina/toxicidade , Inulina/farmacologia , Suplementos Nutricionais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controleRESUMO
In a search for novel nonsugar α-glucosidase inhibitors for diabetes treatment, a series of N-(phenylsulfonyl)thiazole-2-carboxamide derivatives were designed and synthesized, the α-glucosidase inhibitory activities were then evaluated. Several compounds with promising α-glucosidase inhibitory effects were identified. Among these, compound W24 which shows low cytotoxicity and good α-glucosidase inhibitory activity with an IC50 value of 53.0 ± 7.7 µM, is more competitive compared with the commercially available drug acarbose (IC50 = 228.3 ± 9.2 µM). W24 was identified as a promising candidate in the development of α-glucosidase inhibitors. Molecular docking studies and molecular dynamics simulation were also performed to reveal the binding pattern of the active compound to α-glucosidase, and the binding free energy of the best compound W24 was 36.3403 ± 3.91 kcal/mol.
Assuntos
Inibidores de Glicosídeo Hidrolases , Tiazóis , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiazóis/farmacologia , Tiazóis/química , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo , Estrutura MolecularRESUMO
Takotsubo syndrome (TTS) is a stress-induced cardiomyopathy that presents with sudden onset of chest pain and dyspneic and cardiac dysfunction as a result of extreme physical or emotional stress. The sigma-1 receptor (Sigmar1) is a ligand-dependent molecular chaperone that is postulated to be involved in various processes related to cardiovascular disease. However, the role of Sigmar1 in TTS remains unresolved. In this study, we established a mouse model of TTS using wild-type and Sigmar1 knockout mice to investigate the involvement of Sigmar1 in TTS development. Our results revealed that Sigmar1 knockout exacerbated cardiac dysfunction, with a noticeable decrease in ejection fraction (EF) and fractional shortening (FS) compared to the wild-type model. In terms of the gut microbiome, we observed regulation of Firmicutes and Bacteroidetes ratios; suppression of probiotic Lactobacillus growth; and a rise in pathogenic bacterial species, such as Colidextribacter. Metabolomic and transcriptomic analyses further suggested that Sigmar1 plays a role in regulating tryptophan metabolism and several signaling pathways, including MAPK, HIF-1, calcium signaling, and apoptosis pathways, which may be crucial in TTS pathogenesis. These findings offer valuable insight into the function of Sigmar1 in TTS, and this receptor may represent a promising therapeutic target for TTS.
RESUMO
Pseudomonas aeruginosa with difficult-to-treat resistance has been designated as an urgent or serious threat by the CDC in the United States; therefore, novel antibacterial drugs and combination strategies are urgently needed. The sensor kinase RoxS is necessary for the aerobic growth of Pseudomonas aeruginosa. This study aimed to screen candidate RoxS inhibitors and evaluate their efficacy in treating multi-drug-resistant and extensively drug-resistant Pseudomonas aeruginosa in combination with meropenem and amikacin to identify promising combination strategies. RoxS protein structures were constructed using homology modeling and potential RoxS inhibitors, including Ezetimibe, Deferasirox, and Posaconazole, were screened from the FDA-approved ZINC drug database using molecular docking and molecular dynamics simulations. MIC and checkerboard assays were used to determine the in vitro antimicrobial efficacy of the three drugs in combination with antibiotics. The results of in vitro experiments showed an additive effect of 100 µg/mL Deferasirox or 16 µg/mL Posaconazole in combination with meropenem and a synergistic effect of 1.5 µg/mL Deferasirox and amikacin. In summary, these three drugs are potential inhibitors of RoxS, and their combination with meropenem or amikacin is expected to reverse the resistance of P. aeruginosa, providing new combination strategies for the treatment of clinically difficult-to-treat Pseudomonas aeruginosa.
RESUMO
Introduction: Heart failure (HF) is usually the end stage of the continuum of various cardiovascular diseases. However, the mechanism underlying the progression and development of HF remains poorly understood. The sigma-1 receptor (Sigmar1) is a non-opioid transmembrane receptor implicated in many diseases, including HF. However, the role of Sigmar1 in HF has not been fully elucidated. Methods: In this study, we used isoproterenol (ISO) to induce HF in wild-type (WT) and Sigmar1 knockout (Sigmar1-/-) mice. Multi-omic analysis, including microbiomics, metabolomics and transcriptomics, was employed to comprehensively evaluate the role of Sigmar1 in HF. Results: Compared with the WT-ISO group, Sigmar1-/- aggravated ISO-induced HF, including left ventricular systolic dysfunction and ventricular remodeling. Moreover, Sigmar1-/- exacerbated ISO-induced gut microbiota dysbiosis, which was demonstrated by the lower abundance of probiotics g_Akkermansia and g_norank_f_Muribaculaceae, and higher abundance of pathogenic g_norank_f_Oscillospiraceae and Allobaculum. Furthermore, differential metabolites among WT-Control, WT-ISO and Sigmar-/--ISO groups were mainly enriched in bile secretion, tryptophan metabolism and phenylalanine metabolism, which presented a close association with microbial dysbiosis. Corresponding with the exacerbation of the microbiome, the inflammation-related NOD-like receptor signaling pathway, NF-kappa B signaling pathway and TNF signaling pathway were activated in the heart tissues. Conclusion: Taken together, this study provides evidence that a Sigmar1 knockout disturbs the gut microbiota and remodels the serum metabolome, which may exacerbate HF by stimulating heart inflammation.
RESUMO
Organophosphorus flame retardants (OPFRs), including 2-ethylhexyl diphenyl phosphate (EHDPHP), are prevalent in everyday life due to their broad usage in fields such as healthcare, electronics, industry, and sports. These compounds, added to polymers through physical mixing, can leach into the environment, posing a risk to humans through direct contact or the food chain. Despite known associations with health issues like endocrine disruption, neurotoxicity, and reproductive toxicity, the implications of perinatal EHDPHP exposure on both mothers and offspring are still unclear. This study aimed to investigate the neuroinflammatory effects of EHDPHP and the potential mitigating role of inulin. Pregnant C57 mice were administered either a corn oil control or an EHDPHP solution (300 µg/kg bw/d) from gestation day 7 (GD7) to postnatal day 21 (PND21). Concurrently, mice were provided either regular drinking water or water supplemented with 1% inulin. We found that EHDPHP significantly increased the serum levels of IL-1ß, IL-6, and MDA, but decreased SOD levels in both mothers and pups. These effects were reversed by inulin supplementation. RNA-sequencing revealed that EHDPHP induced inflammation and oxidative stress through the TLR4/NF-κB pathway, which was mitigated by inulin. In conclusion, inulin ameliorated EHDPHP-induced neuroinflammation and oxidative stress in both mothers and offspring, highlighting its potential therapeutic role.
Assuntos
Retardadores de Chama , Fosfatos , Gravidez , Camundongos , Humanos , Feminino , Animais , Organofosfatos/toxicidade , Inulina , Doenças Neuroinflamatórias , Estresse Oxidativo , Retardadores de Chama/toxicidadeRESUMO
Polystyrene microplastics (PS-MPs) have emerged as a concerning pollutant in modern society due to their widespread production and usage. Despite ongoing research efforts, the impact of PS-MPs on mammalian behavior and the mechanisms driving these effects remain incompletely elucidated. Consequently, effective strategies for prevention have yet to be developed. To fill these gaps, C57BL/6 mice were orally administered with 5 µm PS-MPs for 28 consecutive days in this study. The open-field test and the elevated plus-maze test were performed to evaluate the anxiety-like behavior, 16S rRNA sequencing and untargeted metabolomics analysis were used to detect the changes of gut microbiota and serum metabolites. Our results indicated that PS-MPs exposure activated hippocampal inflammation and induced anxiety-like behavior in mice. Meanwhile, PS-MPs disturbed the gut microbiota, impaired the intestinal barrier, and aroused peripheral inflammation. Specifically, PS-MPs increased the abundance of pathogenic microbiota Tuzzerella, while lowered the abundance of probiotics Faecalibaculum and Akkermansia. Interestingly, eliminating the gut microbiota protected against the deleterious effects of PS-MPs on intestinal barrier integrity, reduced the levels of peripheral inflammatory cytokines, and ameliorated anxiety-like behavior. Additionally, green tea's primary bioactive constituent, epigallocatechin-3-gallate (EGCG), optimized gut microbial composition, improved intestinal barrier function, reduced peripheral inflammation, and exerted anti-anxiety effects by inhibiting the hippocampal TLR4/MyD88/NF-κB signaling cascade. EGCG also remodeled serum metabolism, especially modulated purine metabolism. These findings suggested that gut microbiota participates in PS-MPs-induced anxiety-like behavior by modulating the gut-brain axis, and that EGCG could serve as a potential preventive strategy.
Assuntos
Microbioma Gastrointestinal , Animais , Camundongos , Camundongos Endogâmicos C57BL , Microplásticos , Plásticos , Poliestirenos/toxicidade , RNA Ribossômico 16S , Homeostase , Inflamação/induzido quimicamente , MamíferosRESUMO
Introduction: Burn injury has been shown to lead to changes in the composition of the gut microbiome and cause other damage in patients. However, little is known about how the gut microbial community evolves in individuals who have recovered from burn injury. Methods: In this study, we established a model of deep partial-thickness burn in mice and collected fecal samples at eight time points (pre-burn, 1, 3, 5, 7, 14, 21, and 28 days post-burn) for 16S rRNA amplification and high-throughput sequencing. Results: The results of the sequencing were analyzed using measures of alpha diversity, and beta diversity and taxonomy. We observed that the richness of the gut microbiome declined from day 7 post-burn and that the principal component and microbial community structure varied over time. On day 28 after the burn, the microbiome composition largely returned to the pre-burn level, although day 5 was a turning point for change. Some probiotics, such as the Lachnospiraceae_NK4A136_group, decreased in composition after the burn but were restored in the later recovery period. In contrast, Proteobacteria showed an opposite trend, which is known to include potential pathogenic bacteria. Conclusion: These findings demonstrate gut microbial dysbiosis after burn injury and provide new insights into the burn-related dysbiosis of the gut microbiome and strategies for improving the treatment of burn injury from the perspective of the microbiota.
RESUMO
As a toxic heavy metal, cadmium (Cd) is one of the principal pollutants influencing rice productivity and food security. Despite several studies, the underlying mechanism of Cd response in plants remains largely unclear. Dehydrins are part of the late embryogenesis abundant (LEA) family which protect plants against abiotic stresses. In this study, a Cd-responsive LEA gene, OsDHN2, was functionally characterized. The chromosome localization results indicated that OsDHN2 was located on chromosome 2 of rice. Meanwhile, cis-acting elements, such as MBS (MYB binding site involved in drought-inducibility), ARE (anaerobic induction), and ABRE (abscisic acid), were present in the OsDHN2 promoter region. Expression pattern analysis also showed that OsDHN2 expression was induced in both roots and shoots under Cd stress. Overexpression of OsDHN2 improved Cd tolerance and reduced Cd concentration in yeast. Moreover, increased expression levels of SOD1, CTA1, GSH1, or CTT1 were found in transgenic yeast under Cd stress, suggesting the increased antioxidant enzymatic activities. These results suggested that OsDHN2 is a Cd-responsive gene that has the potential to improve resistance to Cd in rice.
Assuntos
Cádmio , Oryza , Cádmio/toxicidade , Cádmio/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Oryza/genética , Oryza/metabolismo , Biologia Computacional , Regulação da Expressão Gênica de PlantasRESUMO
Introduction: Depression is a common mental disorder that affects approximately 350 million people worldwide. Much remains unknown about the molecular mechanisms underlying this complex disorder. Sigma-1 receptor (Sig-1R) is expressed at high levels in the central nervous system. Increasing evidence has demonstrated a close association between the Sig-1R and depression. Recently, research has suggested that the gut microbiota may play a crucial role in the development of depression. Methods: Male Sig-1R knockout (Sig-1R KO) and wild-type (WT) mice were used for this study. All transgenic mice were of a pure C57BL/6J background. Mice received a daily gavage of vancomycin (100 mg/kg), neomycin sulfate (200 mg/kg), metronidazole (200 mg/kg), and ampicillin (200 mg/kg) for one week to deplete gut microbiota. Fecal microbiota transplantation (FMT) was conducted to assess the effects of gut microbiota. Depression-like behaviors was evaluated by tail suspension test (TST), forced swimming test (FST) and sucrose preference test (SPT). Gut microbiota was analyzed by 16s rRNA and hippocampal transcriptome changes were assessed by RNA-seq. Results: We found that Sig-1R knockout induced depression-like behaviors in mice, including a significant reduction in immobility time and an increase in latency to immobility in the FST and TST, which was reversed upon clearance of gut microbiota with antibiotic treatment. Sig-1R knockout significantly altered the composition of the gut microbiota. At the genus level, the abundance of Alistipes, Alloprevotella, and Lleibacterium decreased significantly. Gut microbiota dysfunction and depression-like phenotypes in Sig-1R knockout mice could be reproduced through FMT experiments. Additionally, hippocampal RNA sequencing identified multiple KEGG pathways that are associated with depression. We also discovered that the cAMP/CREB/BDNF signaling pathway is inhibited in the Sig-1R KO group along with lower expression of neurotrophic factors including CTNF, TGF-α and NGF. Fecal bacteria transplantation from Sig-1R KO mice also inhibited cAMP/CREB/BDNF signaling pathway. Discussion: In our study, we found that the gut-brain axis may be a potential mechanism through which Sig-1R regulates depression-like behaviors. Our study provides new insights into the mechanisms by which Sig-1R regulates depression and further supports the concept of the gut-brain axis.
RESUMO
Methamphetamine (METH) is a psychotropic drug known to cause cardiotoxicity. The gut-heart axis is emerging as an important pathway linking gut microbiota to cardiovascular disease, but the precise association between METH-induced cardiotoxicity and gut microbiota has yet to be elucidated. In this study, we established an escalating dose-multiple METH administration model in male BALB/c mice, examined cardiac injury and gut microbiota, and investigated the contribution of gut microbiota to cardiotoxicity induced by METH. Additionally, we treated mice with antibiotics and fecal microbiota transplantation (FMT) to assess the impact of gut microbiota on cardiotoxicity. Our results showed that METH exposure altered the p53 and PI3K/Akt signaling pathways and modulated the apoptosis pathway in heart tissue, accompanied by elevated levels of Bax/BCL-2 expression and cleaved caspase-3 proteins. METH exposure increased the diversity and richness of gut microbiota, and significantly changed the microbial community composition, accompanied by elevated abundance of Lactobacillus, Bifidobacterium, and decreased abundance of Bacteroides, norank_f_Muribaculaceae and Alistipes. Eliminating gut microbiota by antibiotics treatment alleviated METH-induced cardiotoxicity, while FMT treatment transferred similar cardiac injury manifestations from METH-exposed mice to healthy recipient mice. Our study unveils the crucial involvement of gut microbiota in the development of cardiotoxicity induced by METH and provides potential strategies for treating cardiac complications caused by METH.
Assuntos
Microbioma Gastrointestinal , Metanfetamina , Masculino , Camundongos , Animais , Metanfetamina/toxicidade , Cardiotoxicidade , Fosfatidilinositol 3-Quinases , AntibacterianosRESUMO
Methamphetamine (Meth) abuse can cause severe anxiety disorder and interfere with gut homeostasis. Obeticholic acid (OCA) has emerged as a protective agent against diet-related anxiety that improves gut homeostasis. The potential for OCA to ameliorate Meth-induced anxiety, and the microbial mechanisms involved, remain obscure. Here, C57/BL6 mice were intraperitoneally injected with Meth (15 mg/kg) to induce anxiety-like behavior. 16 S rRNA sequence analysis and fecal microbiome transplantation (FMT) were used to profile the gut microbiome and evaluate its effects, respectively. Orally administered OCA was investigated for protection against Meth-induced anxiety. Results indicated that Meth mediated anxiety-like behavior, aroused hippocampal neuroinflammation through activation of the TLR4/MyD88/NF-κB pathway, weakened intestinal barrier and disturbed the gut microbiome. Specifically, abundance of anxiety-related Rikenella was increased. FMT from Meth-administrated mice also weakened intestinal barrier and elevated serum LPS, inducing hippocampal neuroinflammation and anxiety-like behavior in recipient mice. Finally, OCA pretreatment ameliorated Meth-induced impairment of gut homeostasis by reshaping the microbial composition and improving the intestinal barrier. Meth-induced anxiety-like behavior and hippocampal neuroinflammation were also ameliorated by OCA pretreatment. These preliminary findings reveal the crucial role of gut microbiota in Meth-induced anxiety-like behavior and neuroinflammation, highlighting OCA as a potential candidate for the prevention of Meth-induced anxiety.
Assuntos
Metanfetamina , Microbiota , Camundongos , Animais , Metanfetamina/toxicidade , Doenças Neuroinflamatórias , Ansiedade/induzido quimicamente , Ansiedade/prevenção & controleRESUMO
BACKGROUND: Compared with the stomach of ruminant cattle, the stomach of horse is small and mainly for chemical digestion, but the microorganisms in the stomach play an important role in maintaining the homeostasis of the internal environment. Due to the complexity of the microbes in the stomach, little is known about the diversity and structure of bacteria in the equine stomach. Grains are the main energy source for plant-eating livestock and energy is derived through enzymatic hydrolysis of grains into glucose or their microbial fermentation into Volatile fatty acids (VFA). However, the mechanism through which these ingested grains are chemically digested as well as the effect of these grains on the stomach remains elusive. This study explored the effects of feeding different grains (corn, oats, and barley) on bacterial diversity, structure, and composition in the foal's stomach content. Furthermore, the effects of different grains on the vitality of starch digestion-related stomach enzymes were investigated. RESULTS: No significant differences were observed (P > 0.05) in the bacterial rarefaction curves of Operational Taxonomic Units (OTUs) and diversity of the stomach microbiota in all foals. This study also revealed the statistical differences for Firmicutes, Cyanobacteria, Actinobacteria, Fibrobacteres, Lactobacillaceae, Streptococcaceae, Unidentified_Clostridiales, Prevotellaceae, Lactobacillus, Streptococcus, Unidentified_Cyanobacteria, Unidentified_Clostridiales, Lactococcus, Sphingomonas, Lactobacillus_hayakitensis, Lactobacillus_equigenerosi, and Clostridium_perfringens. The linear discriminant analysis effect size analysis revealed 9 bacteria at each classification level. The functional analysis of species information by using FAPROTAX software was able to predict 35 functions, and the top 5 functions were chemoheterotrophy, fermentation, animal_parasites_or_symbionts, nitrate_reduction, and aerobic_chemoheterotrophy. The study also revealed statistical differences for pH, glucose concentration, ß-amylase, maltase, and amylase. CONCLUSIONS: The different grains had no significant effect on the microbial diversity of the stomach content of the foal. However, the relative bacterial abundances differed significantly in response to different diets. Particularly, oats fed to the foals significantly increased the relative abundance of Firmicutes, Lactobacillaceae, Lactobacillus, and Lactobacillus_hayakitensis. The grain had no significant effect on the pH of the stomach content, glucose concentration, and enzyme viability in the foal.
Assuntos
Ração Animal , Bactérias , Digestão , Amido , Estômago , Animais , Bactérias/classificação , Grão Comestível , Glucose , Cavalos , Amido/metabolismo , Estômago/metabolismo , Estômago/microbiologiaRESUMO
RATIONALE: Central retinal artery occlusion (CRAO) sparing the cilioretinal artery (CLRA) with severe subretinal fluid and non-characteristic cherry-red spot is uncommon. In the present case, the patient received an intravitreal injection of anti- vascular endothelial growth factor, which is very rare. PATIENT CONCERNS: A 59-year-old man underwent vitrectomy of the left eye for diabetic retinopathy and vitreous hemorrhage. Six months after the operation, the patient presented with sudden painless visual-acuity decline in his left eye and was diagnosed with CRAO; his best corrected visual acuity was weak light perception. Whole retinal edema was seen on the fundus, and macular gray retinal opacification was present without a characteristic cherry-red spot. Optical coherence tomography revealed subretinal fluid (SRF) in the papillomacular bundle and inner retinal thickening. Fundus fluorescein angiography confirmed that the central retinal artery was not filled at 40 seconds and that the CLRA supplied a part of the macular area. Eight months after the second intravitreal injection of ranibizumab, Optical coherence tomography showed a significant reduction in inner retinal hyperreflectivity and the thickness of the nasal macular retina. The SRF was clearly absorbed, and the visual acuity improved to 1.1 logMAR units. DIAGNOSIS: Atypical CRAO. INTERVENTIONS: The patient was treated with intravitreal injection of anti-VEGF in his left eye. The thickness of the nasal macular retina decreased. OUTCOMES: The SRF was clearly absorbed, and the patient's visual acuity significantly improved. LESSONS: When CRAO occurs in patients with diabetic retinopathy sparing the CLRA, the non-characteristic cherry-red spot may be due to macular inner retinal edema, SRF and other factors. According to the patient's condition, anti-vascular endothelial growth factor can be administered as appropriate to inhibit choroidal neovascularization, reduce SRF in the macular retina, and save some vision.