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Copper ionophore NSC319726 has attracted researchers' attention in treating diseases, particularly cancers. However, its potential effects on male reproduction during medication are unclear. This study aimed to determine whether NSC319726 exposure affected the male reproductive system. The reproductive toxicity of NSC319726 was evaluated in male mice following a continuous exposure period of 5 weeks. The result showed that NSC319726 exposure caused testis index reduction, spermatogenesis dysfunction, and architectural damage in the testis and epididymis. The exposure interfered with spermatogonia proliferation, meiosis initiation, sperm count, and sperm morphology. The exposure also disturbed androgen synthesis and blood testis barrier integrity. NSC319726 treatment could elevate the copper ions in the testis to induce cuproptosis in the testis. Copper chelator rescued the elevated copper ions in the testis and partly restored the spermatogenesis dysfunction caused by NSC319726. NSC319726 treatment also decreased the level of retinol dehydrogenase 10 (RDH10), thereby inhibiting the conversion of retinol to retinoic acid, causing the inability to initiate meiosis. Retinoic acid treatment could rescue the meiotic initiation and spermatogenesis while not affecting the intracellular copper ion levels. The study provided an insight into the bio-safety of NSC319726. Retinoic acid could be a potential therapy for spermatogenesis impairment in patients undergoing treatment with NSC319726.
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Cobre , Espermatogênese , Testículo , Tretinoína , Masculino , Animais , Espermatogênese/efeitos dos fármacos , Tretinoína/farmacologia , Cobre/toxicidade , Camundongos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Espermatogônias/efeitos dos fármacos , Espermatogônias/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Meiose/efeitos dos fármacos , Epididimo/efeitos dos fármacos , Epididimo/metabolismo , Epididimo/patologiaRESUMO
Organic frameworks face a trade-off between the framework stability and the bond dynamics, which necessitates the development of innovative linkages that can generate stable frameworks without hindering efficient synthesis. Although iodine(I)-based halogen-bonded organic frameworks (XOFs) have been developed, constructing XOFs based on bromine(I) is desirable yet challenging due to the high sensitivity of bromine(I) species. In this work, we present the inaugural construction of stable bromine(I)-bridged two-dimensional (2D) halogen-bonded organic frameworks, XOF(Br)-TPy-BF4/OTf, based on sensitive [Nâ â â Brâ â â N]+ halogen bonds. The formation of XOF(Br)-TPy-BF4/OTf was monitored by 1H NMR, XPS, IR, SEM, TEM, HR-TEM, SEAD. Their framework structures were established by the results from PXRD, theoretical simulations and SAXS. More importantly, XOF(Br) displayed excellent chemical and thermal stabilities. They exhibited stable two-dimensional framework structures in various organic solvents and aqueous media, even over a wide pH range (pH 3-12), while the corresponding model compounds BrPy2BF4/OTf decomposed quickly even in the presence of minimal water. Furthermore, the influence of the counterions were investigated by replacing BF4 with OTf, which improved the stability of XOF(Br). This characteristic enabled XOF(Br) to serve as an efficient oxidizing reagent in aqueous environments, in contrast with the sensitivity of BrPy2BF4/OTf, which performed well only in organic media. This study not only deepens our fundamental understanding of organic frameworks but also opens new avenues for the development and application of multifunctional XOFs.
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The gut microbiota is increasingly considered to play a key role in human immunity and health. The aging process alters the microbiota composition, which is associated with inflammation, reactive oxygen species (ROS), decreased tissue function, and increased susceptibility to age-related diseases. It has been demonstrated that plant polysaccharides have beneficial effects on the gut microbiota, particularly in reducing pathogenic bacteria abundance and increasing beneficial bacteria populations. However, there is limited evidence of the effect of plant polysaccharides on age-related gut microbiota dysbiosis and ROS accumulation during the aging process. To explore the effect of Eucommiae polysaccharides (EPs) on age-related gut microbiota dysbiosis and ROS accumulation during the aging process of Drosophila, a series of behavioral and life span assays of Drosophila with the same genetic background in standard medium and a medium supplemented with EPs were performed. Next, the gut microbiota composition and protein composition of Drosophila in standard medium and the medium supplemented with EPs were detected using 16S rRNA gene sequencing analysis and quantitative proteomic analysis. Here, we show that supplementation of Eucommiae polysaccharides (EPs) during development leads to the life span extension of Drosophila. Furthermore, EPs decreased age-related ROS accumulation and suppressed Gluconobacter, Providencia, and Enterobacteriaceae in aged Drosophila. Increased Gluconobacter, Providencia, and Enterobacteriaceae in the indigenous microbiota might induce age-related gut dysfunction in Drosophila and shortens their life span. Our study demonstrates that EPs can be used as prebiotic agents to prevent aging-associated gut dysbiosis and reactive oxidative stress.
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Drosophila , Disbiose , Humanos , Animais , Idoso , Drosophila/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Disbiose/tratamento farmacológico , RNA Ribossômico 16S/genética , Proteômica , Polissacarídeos/farmacologia , Envelhecimento , Enterobacteriaceae , Expectativa de VidaRESUMO
The study of long non-coding RNAs (lncRNA) is a newly established field and our knowledge about them is rapidly growing. These kinds of RNAs are unchanged parts of the genome throughout evolution, that modulate cell growth, differentiation, and apoptosis during diverse physiological and pathological processes including leukemia development. They have the capability to be useful biomarkers for the diagnosis, clinical typing, prognosis, as well as potential therapeutic targets. In this study, we summarized the role of lncRNAs in the expression and function of white blood cells and oncogenic transformation into four main types of leukemia.
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Biomarcadores Tumorais/metabolismo , Proliferação de Células , Leucemia/metabolismo , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Humanos , Leucemia/genética , Leucemia/terapia , RNA Longo não Codificante/genética , RNA Neoplásico/genéticaRESUMO
PURPOSE: To evaluate the effectiveness and safety of unilateral pedicle screw fixation in transforaminal lumbar interbody fusion (TLIF) by comparing with bilateral pedicle screw fixation. MATERIALS AND METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trial database were used to search and identify clinical prospective trials that evaluated the efficacy and safety of unilateral fixation as compared with bilateral fixation in TLIF surgery. The methodological qualities of studies were assessed using the PEDro (Physiotherapy Evidence Database) score and Newcastle-Ottawa Scale. RESULTS: Fourteen prospective studies comprising 954 participants were analyzed. Data synthesis show lower fusion rate (P = 0.03) and more cage migration (P = 0.04) in unilateral group compared to bilateral group. There was no significant difference in visual analog scale (VAS), Oswestry Disability Index (ODI), the Short Form 36 Health Survey (SF-36) physical component score (PCS), and length of hospital stay between unilateral and bilateral groups. The unilateral group had shorter operative time (P < 0.00001) and less blood loss (P = 0.0007). CONCLUSIONS: Based on this systematic review and meta-analysis, the unilateral fixation in TLIF may achieve a similar clinical outcome and reduce blood loss and operative time when compared with that in bilateral fixation. However, the unilateral fixation may produce lower fusion rate and more cage migration than bilateral fixation in TLIF.
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Degeneração do Disco Intervertebral/cirurgia , Vértebras Lombares/cirurgia , Parafusos Pediculares , Fusão Vertebral/métodos , Perda Sanguínea Cirúrgica , Humanos , Tempo de Internação , Duração da Cirurgia , Medição da Dor , Estudos Prospectivos , Resultado do Tratamento , Escala Visual AnalógicaRESUMO
BACKGROUND: Spinal cord injury (SCI) is a traumatic neurological disorder with limited therapeutic options. Tumor protein p53-inducible nuclear protein 2 (TP53INP2) is involved in the occurrence and development of various diseases, and it may play a role during SCI via affecting inflammation and neuronal apoptosis. This study investigated the associated roles and mechanisms of TP53INP2 in SCI. METHODS: Mouse and lipopolysaccharide (LPS)-induced SCI BV-2 cell models were constructed to explore the role of TP53INP2 in SCI and the associated mechanisms. Histopathological evaluation of spinal cord tissue was detected by hematoxylin and eosin staining. The Basso, Beattie, and Bresnahan score was used to measure the motor function of the mice, while the spinal cord water content was used to assess spinal cord edema. The expression of TP53INP2 was measured using RT-qPCR. In addition, inflammatory factors in the spinal cord tissue of SCI mice and LPS-treated BV-2 cells were measured using enzyme-linked immunosorbent assay. Apoptosis and related protein expression levels were detected by flow cytometry and western blot analysis, respectively. RESULTS: TP53INP2 levels increased in SCI mice and LPS-treated BV-2 cells. The results of in vivo and in vitro experiments showed that TP53INP2 knockdown inhibited the inflammatory response and neuronal apoptosis in mouse spinal cord tissue or LPS-induced BV-2 cells. CONCLUSIONS: After spinal cord injury, TP53INP2 was upregulated, and TP53INP2 knockdown inhibited the inflammatory response and apoptosis.
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Apoptose , Inflamação , Traumatismos da Medula Espinal , Animais , Masculino , Camundongos , Linhagem Celular , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Inflamação/patologia , Inflamação/metabolismo , Inflamação/genética , Inflamação/imunologia , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Medula Espinal/patologia , Medula Espinal/metabolismo , Medula Espinal/imunologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/genéticaRESUMO
Polypeptide N-Acetylgalactosaminyltransferase (GALNTs) are critical enzymes that initiate mucin type-O glycosylation, and are closely associated with the occurrence and development of multiple cancers. However, the significance of GALNT2 in clear cell renal cell carcinoma (ccRCC) progression remains largely undetermined. Based on public multi-omics analysis, GALNT2 was strongly elevated in ccRCC versus adjoining nontumor tissues, and it displayed a relationship with poor overall survival (OS) of ccRCC patients. In addition, GALNT2 over-expression accelerated proliferation of renal cancer cell (RCC) lines. In contrast, GALNT2 knockdown using shRNAs suppressed cell proliferation, and this was rescued by LATS2 knockdown. Similarly, GALNT2 deficiency enhanced p-LATS2/LATS2 expression. LATS2 is activated by phosphorylation (p-LATS2) and, in turn, phosphorylate the downstream substrate protein YAP. Phosphorylated YAP (p-YAP) stimulated its degradation and cytoplasmic retention, as it was unable to translocate to the nucleus. This resulted in reduced cell proliferation. Subsequently, we explored the upstream miRNAs of GALNT2. Using dual luciferase reporter assay, we revealed that miR-139-5p interacted with the 3' UTR of GALNT2. Low miR-139-5p expression was associated with worse ccRCC patient outcome. Based on our experiments, miR-139-5p overexpression inhibited RCC proliferation, and this phenotype was rescued by GALNT2 overexpression. Given these evidences, the miR-139-5p-GALNT2-LATS2 axis is critical for RCC proliferation, and it is an excellent candidate for a new therapeutic target in ccRCC.
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Stimuli-responsive supramolecular chemotherapy, particularly in response to cancer biomarkers, has emerged as a promising strategy to overcome the limitations associated with traditional chemotherapy. Spermine (SPM) is known to be overexpressed in certain cancers. In this study, we introduced a novel supramolecular chemotherapy system triggered by SPM. The system featured pyridine salts of a diphenylanthracene derivative (PyEn) and a complementary water-soluble pillar[5]arene (WP5C5) with long alkyl chains. The diphenylanthracene unit of PyEn is effectively encapsulated within the long alkyl chains of WP5C5, resulting in a substantial reduction in the cytotoxicity of PyEn towards normal cells. The therapeutic effect of PyEn is selectively triggered intracellularly through SPM, leading to the endosomal release of PyEn and concurrent in situ cytotoxicity. This supramolecular chemotherapy system exhibits notable tumor inhibition against SPM-overexpressed cancers with reduced side effects on normal tissues. The supramolecular strategy for intracellular activation provides a novel tool with potential applications in chemotherapeutic interventions, offering enhanced selectivity and reduced cytotoxicity to normal cells.
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Antracenos , Antineoplásicos , Calixarenos , Compostos de Amônio Quaternário , Solubilidade , Espermina , Água , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Calixarenos/química , Calixarenos/farmacologia , Água/química , Antracenos/química , Espermina/química , Espermina/farmacologia , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Tensoativos/química , Tensoativos/farmacologia , Tensoativos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Tamanho da PartículaRESUMO
Recently, conductive composites have been used in flexible electronic devices and have attracted attention. The integration of self-healing, high sensitivity, large tensile strength, environmental stability, and easy recyclability into conductive composites is very desirable yet challenging. Hence, a conductive composite as a flexible strain sensor with a self-healing and recyclability is facilely developed, with a polyurethane (PU) elastomer bearing dynamic boronic ester as the polymer matrix and carbon nanotubes (CNTs) as a conductive filler. Due to the dynamic boronic ester bond and hydrogen bond, the prepared polyurethane conductive composite has good self-healing and mechanical properties. It not only has a high healing efficiency of 78 % but also has a tensile strength of 15.4 MPa and an elongation at break of 420 %. In addition, the prepared conductive composite has high conductivity (0.57 mS/cm) and sensitivity. As a wearable sensor, it can identify human activities in all directions, such as elbow and finger bending, speaking, and facial changes. Consequently, the polyurethane conductive composite prepared in this study exhibited wonderful application potential in wearable electronic devices such as self-healing strain sensors.
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Nanotubos de Carbono , Dispositivos Eletrônicos Vestíveis , Humanos , Poliuretanos , Condutividade Elétrica , ÉsteresRESUMO
Stability is a fundamental ecological property of the gut microbiota and is associated with host health. Numerous studies have shown that unbalanced dietary components disturb the gut microbial composition and thereby contribute to the onset and progression of disease. However, the impact of unbalanced diets on the stability of the gut microbiota is poorly understood. In the present study, four-week-old mice were fed a plant-based diet high in refined carbohydrates or a high-fat diet for four weeks to simulate a persistent unbalanced diet. We found that persistent unbalanced diets significantly reduced the gut bacterial richness and increased the complexity of bacterial co-occurrence networks. Furthermore, the gut bacterial response to unbalanced diets was phylogenetically conserved, which reduced network modularity and enhanced the proportion of positive associations between community taxon, thereby amplifying the co-oscillation of perturbations among community species to destabilize gut microbial communities. The disturbance test revealed that the gut microbiota of mice fed with unbalanced diets was less resistant to antibiotic perturbation and pathogenic bacteria invasion. This study may fill a gap in the mechanistic understanding of the gut microbiota stability in response to diet and provide new insights into the gut microbial ecology.
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Supramolecular organic frameworks (SOFs) have emerged as a promising class of organic porous materials with vast potential as nanocarriers for combination therapy. Here, we successfully construct an anionic flexible supramolecular organic framework (TPP-SOF) by leveraging multiple host-guest interactions. TPP-SOF is fabricated by the hierarchical orthogonal assembly between anionic water-soluble dimacrocyclic host (P5CD), porphyrin photosensitizers (TPP), and ROS-sensitive thioketal linked adamantane dimer (Ada-S-Ada). TPP-SOF exhibits pH-dependent activation of 1O2 production, which further facilitates the cleavage of Ada-S-Ada linker and promotes the disintegration of the framework. Moreover, leveraging electrostatic and hydrophobic interactions, the anionic TPP-SOF serves as an effective platform for loading cationic photosensitizer IR780 and chemotherapeutic prodrug PhenPt(IV), leading to the formation of supramolecular nanoparticles (IR780/Pt@TPP-SOF) for synergistic therapy. The obtained nanoparticles exhibit good stability, efficient generation of 1O2, and photothermal performance. In vitro and in vivo studies indicate that IR780/Pt@TPP-SOF exhibits remarkable synergistic chemo/PDT/PTT effects under 808 and 660 nm light irradiation. This study showcases a deep insight for the development of SOFs and a new approach for delivering cationic drugs and constructing synergistic combination therapy systems. STATEMENT OF SIGNIFICANCE: In this work, a pH/ROS-responsive anionic flexible supramolecular organic framework, TPP-SOF, was innovatively designed by the hierarchical orthogonal assembly, to co-deliver cationic photosensitizer IR780 and prodrug PhenPt(IV) for synergistic cancer therapy. The drug-loaded TPP-SOF is termed IR780/Pt@TPP-SOF, in which the photoactivity of porphyrin within TPP-SOF could be activated under acidic conditions, the 1O2 generated by the photosensitizers could break the thioketal bonds in Ada-S-Ada, leading to the disassembly of the framework and releasing the drugs. This supramolecular drug delivery system displays good biocompatibility and exhibits remarkable synergistic chemo/PDT/PTT effects.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Porfirinas , Pró-Fármacos , Humanos , Fármacos Fotossensibilizantes/química , Pró-Fármacos/química , Espécies Reativas de Oxigênio/química , Polímeros/química , Nanopartículas/química , Porfirinas/farmacologia , Porfirinas/química , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológicoRESUMO
Ionic conductive hydrogels (ICHs) have received widespread attention as an ideal candidate for flexible electronic devices. However, conventional ICHs failed in widespread applications due to their inability to simultaneously possess high toughness, high ionic conductivity, and anti-freezing properties. Here, polyvinyl alcohol (PVA) and polyacrylamide (PAAm) were first dissolved in the zinc chloride solution, in which zinc ions (Zn2+) act as ionic cross-linkers and conducting ions, followed by the introduction of xanthan gum (XG) with a unique structure of trisaccharide side chains into the PVA/PAAm semi-interpenetrating network to prepare a dual-network ICHs (refers as PPXZ). Enabled by the synergistic effect of intermolecular chemical covalent cross-linking and physical cross-linking, PPXZ hydrogels exhibit significantly improved mechanical properties without sacrificing electrical conductivity. Furthermore, PPXZ hydrogels are successfully applied to flexible electronic devices, such as strain sensors and zinc ion hybrid supercapacitors, exhibiting satisfactory sensing sensitivity and cycling stability at a wide temperature range, respectively. Even at a high current density (10 A g-1), the capacity of the supercapacitor retains 88.24 % after 10,000 cycles. This strategy provides new insight for ICHs in wide temperature-applied flexible electronic devices.
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Eletrônica , Álcool de Polivinil , Condutividade Elétrica , Hidrogéis , ÍonsRESUMO
SCOPE: This study aims to investigate the role of gut microbiota regulation with ketogenic diet (KD) in hypoglycemia-induced neuroinflammation. METHODS AND RESULTS: Immunofluorescence staining and western blotting show that KD alleviates blood-brain barrier injury induced by hypoglycemia by increasing Podxl and zonula occludens-1 (ZO-1) levels. KD-fed mice show reduced brain edema by decreasing aquaporin-4 (AQP4) content and maintaining its polarized expression. 16S rRNA gene amplicon sequencing results show that KD reduces the Chao 1 index of gut microbiota α-diversity, and significant separation is detected in the ß-diversity analysis between the control and KD-fed mice. KD increases the relative abundance of Firmicutes and Proteobacteria and decreases that of Bacteroidetes. Hypoglycemia can reduce SOD and GSH-PX levels while increasing TNF-α, IL-1ß, and IL-6 mRNA levels in the brain tissues of mice. KD alleviates hypoglycemia-induced neuroinflammation by inhibiting microglia activation and TLR4/p38MAPK/NF-κB signaling pathway. Importantly, antibiotic cocktail depletion of the gut microbiota weakens anti-inflammatory and antioxidation responses in KD-fed mice. CONCLUSION: Collectively, these findings suggest that KD alleviates hypoglycemia-induced brain injury via gut microbiota modulation, which may provide novel insights into the therapy for hypoglycemia.
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Dieta Cetogênica , Microbioma Gastrointestinal , Hipoglicemia , Camundongos , Animais , Doenças Neuroinflamatórias , RNA Ribossômico 16SRESUMO
BACKGROUND: Aberrant tryptophan (Trp)-kynurenine (Kyn) metabolism has been implicated in the pathogenesis of human disease. In particular, populations with long-term western-style diets are characterized by an excess of Kyn in the plasma. Host-gut microbiota interactions are dominated by diet and are essential for maintaining host metabolic homeostasis. However, the role of western diet-disturbed gut microbiota-colonocyte interactions in Trp metabolism remains to be elucidated. RESULTS: Here, 4-week-old mice were fed with a high-fat diet (HFD), representing a typical western diet, for 4 weeks, and multi-omics approaches were adopted to determine the mechanism by which HFD disrupted gut microbiota-colonocyte interplay causing serum Trp-Kyn metabolism dysfunction. Our results showed that colonocyte-microbiota interactions dominated the peripheral Kyn pathway in HFD mice. Mechanistically, persistent HFD-impaired mitochondrial bioenergetics increased colonic epithelial oxygenation and caused metabolic reprogramming in colonites to support the expansion of Proteobacteria in the colon lumen. Phylum Proteobacteria-derived lipopolysaccharide (LPS) stimulated colonic immune responses to upregulate the indoleamine 2,3-dioxygenase 1 (IDO1)-mediated Kyn pathway, leading to Trp depletion and Kyn accumulation in the circulation, which was further confirmed by transplantation of Escherichia coli (E.coli) indicator strains and colonic IDO1 depletion. Butyrate supplementation promoted mitochondrial functions in colonocytes to remodel the gut microbiota in HFD mice, consequently ameliorating serum Kyn accumulation. CONCLUSIONS: Our results highlighted that HFD disrupted the peripheral Kyn pathway in a gut microbiota-dependent manner and that the continuous homeostasis of gut bacteria-colonocytes interplay played a central role in the regulation of host peripheral Trp metabolism. Meanwhile, this study provided new insights into therapies against western diet-related metabolic disorders. Video Abstract.
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Microbioma Gastrointestinal , Triptofano , Humanos , Animais , Camundongos , Triptofano/metabolismo , Cinurenina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Colo/microbiologiaRESUMO
On-skin hydrogel electrodes are poorly conformable in sweaty scenarios due to low electrode-skin adhesion resulting from the sweat film formed on the skin surface, which seriously hinders practical applications. In this study, we fabricated a tough adhesive cellulose-nanofibril/poly(acrylic acid) (CNF/PAA) hydrogel with tight hydrogen-bond (H-bond) networks based on a common monomer and a biomass resource. Furthermore, inherent H-bonded network structures can be disrupted through judicious engineering using excess hydronium ions produced through sweating, which facilitate the transition to protonation and modulate the release of active groups (i.e., hydroxyl and carboxyl groups) accompanied by a pH drop. The lower pH enhances adhesive performance, especially on skin, with a 9.7-fold higher interfacial toughness (453.47 vs. 46.74 J m-2), an 8.6-fold higher shear strength (600.14 vs. 69.71 kPa), and a 10.4-fold higher tensile strength (556.44 vs. 53.67 kPa) observed at pH 4.5 compared to the corresponding values at pH 7.5. Our prepared hydrogel electrode remains conformable on sweaty skin when assembled as a self-powered electronic skin (e-skin) and enables electrophysiological signals to be reliably collected with high signal-to-noise ratios when exercising. The strategy presented here promotes the design of high-performance adhesive hydrogels that may serve to record continuous electrophysiological signals under real-life conditions (beyond sweating) for various intelligent monitoring systems.
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Adesivos , Dispositivos Eletrônicos Vestíveis , Adesivos/química , Sudorese , Suor , Hidrogéis , Concentração de Íons de HidrogênioRESUMO
BACKGROUND: Chronic stress alters gut microbiota composition, as well as induces inflammatory responses and behavioral deficits. Eucommiae cortex polysaccharides (EPs) have been reported to remodel gut microbiota and ameliorate obesogenic diet-induced systemic low-grade inflammation, but their role in stress-induced behavioral and physiological changes is poorly understood. METHODS: Male Institute of Cancer Research (ICR) mice were exposed to chronic unpredictable stress (CUMS) for 4 weeks and then supplemented with EPs at a dose of 400 mg/kg once per day for 2 weeks. Behavioral test-specific antidepressant and anxiolytic effects of EPs were assessed in FST, TST, EPM, and OFT. Microbiota composition and inflammation were detected using 16S ribosomal RNA (rRNA) gene sequencing, quantitative RT-PCR, western blot, and immunofluorescence. RESULTS: We found that EPs ameliorated gut dysbiosis caused by CUMS, as evidenced by increasing the abundance of Lactobacillaceae and suppressing the expansion of the Proteobacteria, thereby mitigating intestinal inflammation and barrier derangement. Importantly, EPs reduced the release of bacterial-derived lipopolysaccharides (LPS, endotoxin) and inhibited the microglia-mediated TLR4/NFκB/MAPK signaling pathway, thereby attenuating the pro-inflammatory response in the hippocampus. These contributed to restoring the rhythm of hippocampal neurogenesis and alleviating behavioral abnormalities in CUMS mice. Correlation analysis showed that the perturbed-gut microbiota was strongly correlated with behavioral abnormalities and neuroinflammation. LIMITATIONS: This study did not clarify the causal relationship between EPs remodeling the gut microbiota and improved behavior in CUMS mice. CONCLUSIONS: EPs exert ameliorative effects on CUMS-induced neuroinflammation and depression-like symptoms, which may be strongly related to their beneficial effects on gut microbial composition.
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Depressão , Microbioma Gastrointestinal , Camundongos , Masculino , Animais , Depressão/etiologia , Doenças Neuroinflamatórias , Disbiose/tratamento farmacológico , Disbiose/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Hipocampo/metabolismo , Lipopolissacarídeos/farmacologia , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Modelos Animais de DoençasRESUMO
Fibroepithelial polyp of the ureter is a benign tumor of mesodermal origin that rarely occurs in children. The most common presenting symptoms are hematuria and flank pain by obstruction of the urinary tract. The etiology of this tumor is still not clear. It occurs more frequently in boys and often arises in the proximal ureter and the ureteropelvic junction. The preoperative diagnosis is difficult. We present here the case of a 11-year-old boy who had fibroepithelial polyps as the cause of the left flank ureteropelvic junction obstruction at pyeloplasty, and had the same condition on the right flank 5 years ago. We used polypectomy and pyeloureterostomy to treat the boy. No major intraoperative or preoperative complications developed.
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Neoplasias Fibroepiteliais/diagnóstico , Pólipos/diagnóstico , Neoplasias Ureterais/diagnóstico , Criança , Humanos , Masculino , Neoplasias Fibroepiteliais/patologia , Neoplasias Fibroepiteliais/cirurgia , Pólipos/patologia , Pólipos/cirurgia , Neoplasias Ureterais/patologia , Neoplasias Ureterais/cirurgia , Procedimentos Cirúrgicos Urológicos/métodosRESUMO
KRAS plays critical roles in regulating a range of normal cellular events as well as pathological processes in many tissues mediated through a variety of signaling pathways, including ERK1/2 and AKT signaling, in a cell-, context- and development-dependent manner. The in vivo function of KRAS and its downstream targets in gonadal steroidogenic cells for the development and homeostasis of reproductive functions remain to be determined. To understand the functions of KRAS signaling in gonadal theca and interstitial cells, we generated a Kras mutant (tKrasMT) mouse line that selectively expressed a constitutively active Kras G12D in these cells. Kras G12D expression in ovarian theca cells did not block follicle development to the preovulatory stage. However, tKrasMT females failed to ovulate and thus were infertile. The phosphorylated ERK1/2 and forkhead box O1 (FOXO1) and total FOXO1 protein levels were markedly reduced in tKrasMT theca cells. Kras G12D expression in theca cells also curtailed the phosphorylation of ERK1/2 and altered the expression of several ovulation-related genes in gonadotropin-primed granulosa cells. To uncover downstream targets of KRAS/FOXO1 signaling in theca cells, we found that the expression of bone morphogenic protein 7 (Bmp7), a theca-specific factor involved in ovulation, was significantly elevated in tKrasMT theca cells. Chromosome immunoprecipitation assays demonstrated that FOXO1 interacted with the Bmp7 promoter containing forkhead response elements and that the binding activity was attenuated in tKrasMT theca cells. Moreover, Foxo1 knockdown caused an elevation, whereas Foxo1 overexpression resulted in an inhibition of Bmp7 expression, suggesting that KRAS signaling regulates FOXO1 protein levels to control Bmp7 expression in theca cells. Thus, the anovulation phenotype observed in tKrasMT mice may be attributed to aberrant KRAS/FOXO1/BMP7 signaling in theca cells. Our work provides the first in vivo evidence that maintaining normal KRAS activity in ovarian theca cells is crucial for ovulation and female fertility.
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Numb (Nb) and Numb-like (Nbl) are functionally redundant adaptor proteins that critically regulate cell fate and morphogenesis in a variety of organs. We selectively deleted Nb and Nbl in testicular germ cells by breeding Nb/Nbl floxed mice with a transgenic mouse line Tex101-Cre. The mutant mice developed unilateral or bilateral cystic dilation in the rete testis (RT). Dye trace indicated partial blockages in the testicular hilum. Morphological and immunohistochemical evaluations revealed that the lining epithelium of the cysts possessed similar characteristics of RT epithelium, suggesting that the cyst originated from dilation of the RT lumen. Spermatogenesis and the efferent ducts were unaffected. In comparisons of isolated germ cells from mutants to control mice, the Notch activity considerably increased and the expression of Notch target gene Hey1 significantly elevated. Further studies identified that germ cell Fgf4 expression negatively correlated the Notch activity and demonstrated that blockade of FGF receptors mediated FGF4 signaling induced enlargement of the RT lumen in vitro. The crucial role of the FGF4 signaling in modulation of RT development was verified by the selective germ cell Fgf4 ablation, which displayed a phenotype similar to that of germ cell Nb/Nbl null mutant males. These findings indicate that aberrant over-activation of the Notch signaling in germ cells due to Nb/Nbl abrogation impairs the RT development, which is through the suppressing germ cell Fgf4 expression. The present study uncovers the presence of a lumicrine signal pathway in which secreted/diffusible protein FGF4 produced by germ cells is essential for normal RT development.
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Rationale: The high fat and sucrose diet, known as the obesogenic diet (OD), has been related to low-grade chronic inflammation and neurodevelopmental disorders. Emerging evidence suggests that OD influences cognitive and social function via the gut-brain axis. However, the effects of OD during adolescence on future health have been unclear. Meanwhile, the underlying mechanisms and effective interventions are not fully understood. Polysaccharides, one of the most abundant substances in the Eucommiae cortex, exhibit potential immunomodulatory and neuroprotective effects. Here, we aimed to investigate the impact of OD on adolescents, explore the modulating roles of Eucommiae cortex polysaccharides (EPs) on OD-induced behavioral dysfunction, and elucidate the underlying molecular mechanisms. Methods: In the present study, four-week-old mice were fed with OD for four weeks to simulate persistent OD in adolescents. The behavioral features were accessed by open field test and Morris water maze. The gut bacterial structure was identified by 16S rRNA gene amplicon sequencing. The gene and protein expression in colonic tissues and hippocampus were detected by qRT-PCR, immunoblotting, enzyme-linked immunosorbent assay, and immunofluorescence staining. Detection of biological metabolites in serum and hippocampal tissues was performed by widely targeted metabolomics and targeted metabolomics. Results: We found that OD-fed mice showed cognitive and social-behavioral deficits accompanied by gut dysbiosis and systematic tryptophan (Trp) metabolism disorders, which increased kynurenine (Kyn) concentration in the hippocampus. Bacteria-derived lipopolysaccharide (LPS, endotoxin) induced microglia-mediated neuroinflammation, directing the metabolism of Kyn in the hippocampus toward quinolinic acid (QA), which led to glutamate-mediated hyperactivation of mossy cells (MCs) in hippocampal hilus. Furthermore, OD impaired parvalbumin (PV) interneurons-related local circuits in the hippocampal granule cell layer. These resulted in hippocampal neurogenesis deficits and related behavioral dysfunction in mice. EPs supplementation ameliorated OD-induced gut dysbiosis, as evidenced by inhibiting the expansion of Escherichia coli (E.coli) and reducing the concentration of LPS in colonic contents and serum, thereby inhibiting the subsequent neuroinflammation. In addition, oral EPs suppressed the peripheral Kyn pathway to reduce the concentration of QA and glutamic acid in the hippocampus of OD-fed mice, thereby rescuing the glutamic acid-triggered neuroexcitotoxicity. These contributed to remodeling the rhythm of hippocampal neurogenesis and mitigated behavioral dysfunction in OD-fed mice. Conclusions: The present study addresses a gap in the understanding of neuronal dysfunction associated with OD during adolescence and provides the first evidence that EPs improved cognitive and social behavior via modulation of gut microbiota and tryptophan metabolism in adolescent mice fed with OD, which may represent novel preemptive therapy for neurodevelopmental disorders via manipulation of the tryptophan metabolite.