RESUMEN
Polyphenols are the most prevalent naturally occurring phytochemicals in the human diet and range in complexity from simple molecules to high-molecular-weight polymers. They have a broad range of chemical structures and are generally categorized as "neuroprotective", "anti-inflammatory", and "antioxidant" given their main function of halting disease onset and promoting health. Research has shown that some polyphenols and their metabolites can penetrate the blood-brain barrier and hence increase neuroprotective signaling and neurohormonal effects to provide anti-inflammatory and antioxidant effects. Therefore, multi-targeted modulation of polyphenols may prevent the progression of neuropsychiatric disorders and provide a new practical therapeutic strategy for difficult-to-treat neuropsychiatric disorders. Therefore, multi-target modulation of polyphenols has the potential to prevent the progression of neuropsychiatric disorders and provide a new practical therapeutic strategy for such nervous system diseases. Herein, we review the therapeutic benefits of polyphenols on autism-spectrum disorders, anxiety disorders, depression, and sleep disorders, along with in vitro and ex vivo experimental and clinical trials. Although their methods of action are still under investigation, polyphenols are still seldom employed directly as therapeutic agents for nervous system disorders. Comprehensive mechanistic investigations and large-scale multicenter randomized controlled trials are required to properly evaluate the safety, effectiveness, and side effects of polyphenols.
RESUMEN
Post-stroke depression (PSD) is a psychological disease that can occur following a stroke and is associated with serious consequences. Research on the pathogenesis and treatment of PSD is still in the infancy stage. Patients with PSD often exhibit gastrointestinal symptoms; therefore the role of gut microbiota in the pathophysiology and potential treatment effects of PSD has become a hot topic of research. In this review, describe the research on the pathogenesis and therapy of PSD. We also describe how the gut microbiota influences neurotransmitters, the endocrine system, energy metabolism, and the immune system. It was proposed that the gut microbiota is involved in the pathogenesis and treatment of PSD through the regulation of neurotransmitter levels, vagal signaling, hypothalamic-pituitary-adrenal axis activation and inhibition, hormone secretion and release, in addition to immunity and inflammation.
Asunto(s)
Microbioma Gastrointestinal , Accidente Cerebrovascular , Humanos , Microbioma Gastrointestinal/fisiología , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/microbiología , Depresión/microbiología , Sistema Hipotálamo-Hipofisario/metabolismo , Animales , Sistema Hipófiso-Suprarrenal/metabolismoRESUMEN
Background: This study aimed to clarify the relationship between the gut microbiota and osteoporosis combining Mendelian randomization (MR) analysis with animal experiments. Methods: We conducted an analysis on the relationship between differential bacteria and osteoporosis using open-access genome-wide association study (GWAS) data on gut microbe and osteoporosis obtained from public databases. The analysis was performed using two-sample MR analysis, and the causal relationship was examined through inverse variance weighting (IVW), MR Egger, weighted median, and weighted mode methods. Bilateral oophorectomy was employed to replicate the mouse osteoporosis model, which was assessed by micro computed tomography (CT), pathological tests, and bone transformation indexes. Additionally, 16S rDNA sequencing was conducted on fecal samples, while SIgA and indexes of IL-6, IL-1ß, and TNF-α inflammatory factors were examined in colon samples. Through immunofluorescence and histopathology, expression levels of tight junction proteins, such as claudin-1, ZO-1, and occludin, were assessed, and conduct correlation analysis on differential bacteria and related environmental factors were performed. Results: A positive correlation was observed between g_Ruminococcus1 and the risk of osteoporosis, while O_Burkholderiales showed a negative correlation with the risk of osteoporosis. Furthermore, there was no evidence of heterogeneity or pleiotropy. The successful replication of the mouse osteoporosis model was assessed, and it was found that the abundance of the O_Burkholderiales was significantly reduced, while the abundance of g_Ruminococcus was significantly increased in the ovariectomized (OVX)-mice. The intestinal SIgA level of OVX mice decreased, the expression level of inflammatory factors increased, barrier damage occurred, and the content of LPS in the colon and serum significantly increased. The abundance level of O_Burkholderiales is strongly positively correlated with bone formation factors, gut barrier indicators, bone density, bone volume fraction, and trabecular bone quantity, whereas it was strongly negatively correlated with bone resorption factors and intestinal inflammatory factors, The abundance level of g_Ruminococcus shows a strong negative correlation with bone formation factors, gut barrier indicators, and bone volume fraction, and a strong positive correlation with bone resorption factors and intestinal inflammatory factors. Conclusion: O_Burkholderiales and g_Ruminococcus may regulate the development of osteoporosis through the microbiota-gut-bone axis.
RESUMEN
We previously revealed that Cang-ai volatile oil (CAVO) regulates T-cell activity, enhancing the immune response in people with chronic respiratory diseases. However, the effects of CAVO on allergic rhinitis (AR) have not been investigated. Herein, we established an ovalbumin (OVA)-induced AR rat model to determine these effects. Sprague-Dawley (SD) rats were exposed to OVA for 3 weeks. CAVO or loratadine (positive control) was given orally once daily for 2 weeks to OVA-exposed rats. Behavior modeling nasal allergies was observed. Nasal mucosa, serum, and spleen samples of AR rats were analyzed. CAVO treatment significantly reduced the number of nose rubs and sneezes, and ameliorated several hallmarks of nasal mucosa tissue remodeling: inflammation, eosinophilic infiltration, goblet cell metaplasia, and mast cell hyperplasia. CAVO administration markedly upregulated expressions of interferon-γ, interleukin (IL)-2, and IL-12, and downregulated expressions of serum tumor necrosis factor-α, IL-4, IL-5, IL-6, IL-13, immunoglobulin-E, and histamine. CAVO therapy also increased production of IFN-γ and T-helper type 1 (Th1)-specific T-box transcription factor (T-bet) of the cluster of differentiation-4+ T-cells in splenic lymphocytes, and protein and mRNA expressions of T-bet in nasal mucosa. In contrast, levels of the Th2 cytokine IL-4 and Th2-specific transcription factor GATA binding protein-3 were suppressed by CAVO. These cumulative findings demonstrate that CAVO therapy can alleviate AR by regulating the balance between Th1 and Th2 cells.
RESUMEN
Due to the large mining area, the fully-mechanized top-caving mining with thick-hard roof is easy to form cantilever structure on the lateral roof of the working face, which on the one hand causes high stress level of adjacent roadway and serious deformation of roadway, on the other hand causes gas accumulation in corners, which brings severe challenges to safe and efficient mining of the mine. In this study, a mine facing such problems in Jincheng, China was taken as the research object. Based on the mechanical characteristics of coal and rock, the characteristics of overlying strata activity in the mining process of working face are mastered, and the dual effects of controlled transformation of lateral overlying strata structure on stress field and gas field were revealed. On this basis, roadway reinforcement and gas drainage schemes were put forward and applied. The results showed that the strength of the hard rock stratum was high in the triaxial stress environment, and it was not easily destroyed. However, once the strata exceed their strength threshold, they break down. In addition, the strength of coal is relatively low, and it is continuously deformed when the force exceeds its strength. The overlying strata structure after thick-hard roof fully-mechanized top-caving mining evolves in the following manner: "long cantilever length formed by the main roof being broken in the initial stage, voussoir beam formed by the upper hard roof being broken in the middle stage, and double cantilever beam formed by overlying strata compaction." The stress carried by upper hard rock stratum is transferred to coal pillars, which is the main reason for the high stress environment of multi-purpose roadway with large coal pillars. The controlled transformation of lateral overlying strata structure by pre-splitting and roof cutting can realize the "transfer-unloading" of coal pillar stress and the "plugging and driving" of corner gas. Based on the hydraulic fracturing reconstruction of lateral overburden structure, the grouting reinforcement scheme of roadway and dynamic gas drainage scheme were put forward. The results demonstrated that after roof cutting, the maximum deformation of the surrounding rock in the multi-purpose roadway was reduced by approximately 90 %, and the maximum concentration of corner gas was decreased by 15.28 %. This approach successfully achieved a collaborative control effect on roadway surrounding rock stability and gas emission well within the safety limits.
RESUMEN
Polycystic ovary syndrome (PCOS) is one of the most prevalent gynecological endocrine conditions affecting reproductive women. It can feature a variety of symptoms, such as obesity, insulin resistance, skin conditions, and infertility. Women with PCOS are susceptible to illnesses including mood disorders, diabetes, hypertension, and dyslipidemia. Among them, depression is the most common in PCOS and has a detrimental effect on quality of life. Depression may occasionally develop due to the pathological traits of PCOS, but its exact pathogenesis in PCOS have eluded researchers to date. Therefore, there is an urgent need to explore the pathogenesis and treatments of depression in PCOS. The present review discusses the epidemiology of depression in PCOS, potential pathogenic mechanisms underlying PCOS and depression, as well as some potential factors causing depression in PCOS, including obesity, insulin resistance, hyperandrogenism, inflammation, and infertility. Meanwhile, some common treatment strategies for depression in PCOS, such as lifestyle intervention, acupuncture, oral contraceptive pills, psychological intervention, and insulin-sensitizer, are also reviewed. To fully understand the pathogenesis and treatment of depression in PCOS, a need remains for future large-scale multi-center randomized controlled trials and in-depth mechanism studies. Appeared originally in Front Psychiatry 2022; 13:1001484.
RESUMEN
Objective: To evaluate the effectiveness of different acupuncture treatments for mammary gland hyperplasia (MGH) using a network meta-analysis. Methods: Several databases were searched without language restrictions from 2000 to February 2023, including PubMed, Embase, Web of Science, Cochrane Library, China Science and Technology Journal Database, China Biology Medicine Database, Wanfang Database, China National Knowledge Infrastructure Database, and other professional websites and gray literature. Inclusion criteria were adult women diagnosed with MGH; intervention measures included acupuncture and related therapies; the control group was treated with simple drugs; and the research type was a randomized controlled trial (RCT). The primary outcomes were treatment effectiveness and estradiol and progesterone levels. Secondary outcomes were breast lump size and visual analog scale (VAS) score of breast pain. Exclusion criteria were studies unrelated to MGH, incorrect study populations, control measures or interventions, incomplete data, non-RCTs, case reports, and animal experiments. Cochrane tools were used to assess the risk of bias. The R software (x64 version 4.2.1), Review Manager 5.3 software and STATA 16.0 software were used for data analysis. Results: Following a rigorous screening process, data extraction, and quality assessment, 48 eligible RCTs encompassing 4,500 patients with MGH and 16 interventions were included. The results indicated that acupuncture, alone or in combination with traditional Chinese or Western medicine, had better therapeutic effects than conventional therapy. In terms of effectiveness, warm needle acupuncture was the best choice (94.6%). Bloodletting pricking was the most effective method (85.7%) for lowering progesterone levels. Bloodletting pricking was the most effective method (98.3%) for lowering estradiol levels. Manual acupuncture combined with traditional Chinese medicine was the most effective (74.5%) treatment to improve the size of the breast lump. Warm needle acupuncture was the most effective (69.8%) in improving the VAS score. Conclusion: Acupuncture therapy was more effective in treating MGH than drug therapy alone, and warm needle acupuncture and bloodletting pricking were the two best options. However, larger sample sizes and high-quality RCTs are required.
RESUMEN
Developing highly efficient adsorbents for the removal of trace thallium(I) (Tl+) is crucial for addressing environmental challenges. In this study, we successfully synthesized cubic Prussian blue (PB) loading on filter papers using an intermediate layer (dopamine/polyethyleneimine) via in-situ methods. The as-prepared PB-modified FP demonstrated outstanding anti-interference properties and light-enhanced adsorption performance for Tl+ (0.5 mg/L) under ultraviolet (UV) irradiation, exhibiting twice the effectiveness compared to dark conditions, even in acidic and coexisting ionic environments. This indicated its suitability for treating complex Tl+-contaminated water. Notably, the removal efficiency for trace Tl+ was almost 100%, with a maximum experimental adsorption capacity of 86.2 mg/g after 1-h photo-promoted adsorption under 365 nm UV. Characterization results supported a proposed photo-driven redox mechanism that elucidated the interaction between Tl+ and PB-modified FP. Specifically, the accelerated Fe(III) to Fe(II) redox reaction facilitated Tl+ accommodation on the surface and/or lattice of PB, enhancing Tl+ adsorption by compensating for missed positive charges. This study provides valuable insights into utilizing PB-based materials to enhance the photo-enhanced Tl+ adsorption capacity in a cost-effective, easy-to-synthesize, and environmentally friendly manner.
RESUMEN
Properly design and manufacture of bifunctional electrocatalysts with superb performance and endurance are crucial for overall water splitting. The interfacial engineering strategy is acknowledged as a promising approach to enhance catalytic performance of overall water splitting catalysts. Herein, the Ru nanoparticles modified Ni3Se4/Ni(OH)2 heterostructured nanosheets catalyst was constructed using a simple two-step hydrothermal process. The experimental results demonstrate that the abundant heterointerfaces between Ru and Ni3Se4/Ni(OH)2 can increase the number of active sites and effectively regulate the electronic structure, greatly accelerating the kinetics of the hydrogen evolution reaction (HER)/oxygen evolution reaction (OER). As a result, the Ru/Ni3Se4/Ni(OH)2/NF catalyst exhibits the low overpotential of 102.8 mV and 334.5 mV at 100 mA cm-2 for HER and OER in alkaline medium, respectively. Furthermore, a two-electrode system composed of the Ru/Ni3Se4/Ni(OH)2/NF requires a battery voltage of just 1.51 V at 10 mA cm-2 and remains stable for 200 h at 500 mA cm-2. This work provides an effective strategy for constructing Ru-based heterostructured catalysts with excellent catalytic activity.
RESUMEN
Gouty nephropathy (GN) is a metabolic disease with persistently elevated blood uric acid levels. The main manifestations of GN are crystalline kidney stones, chronic interstitial nephritis, and renal fibrosis. Understanding the mechanism of the occurrence and development of GN is crucial to the development of new drugs for prevention and treatment of GN. Currently, most studies exploring the pathogenesis of GN are primarily based on animal and cell models. Numerous studies have shown that inflammation, oxidative stress, and programmed cell death mediated by uric acid and sodium urate are involved in the pathogenesis of GN. In this article, we first review the mechanisms underlying the abnormal intrinsic immune activation and programmed cell death in GN and then describe the characteristics and methods used to develop animal and cell models of GN caused by elevated uric acid and deposited sodium urate crystals. Finally, we propose potential animal models for GN caused by abnormally high uric acid levels, thereby provide a reference for further investigating the methods and mechanisms of GN and developing better prevention and treatment strategies.
RESUMEN
Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1ß-C/EBPß-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1-486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1-486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1-486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer's disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.
Asunto(s)
Depresión , Hipocampo , Estrés Psicológico , Animales , Hipocampo/metabolismo , Ratones , Depresión/metabolismo , Masculino , Estrés Psicológico/metabolismo , Receptor trkB/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Conducta Animal/fisiología , Transducción de Señal/fisiología , Enfermedad de Alzheimer/metabolismo , Glicoproteínas de Membrana/metabolismoRESUMEN
Objective: Stroke is frequently associated with muscle mass loss. Treadmill training is considered the most effective treatment for sarcopenia. Circadian rhythms are closely related to exercise and have been extensively studied. The skeletal muscle has its molecular clock genes. Exercise may regulate skeletal muscle clock genes. This study evaluated the effects of early treadmill training on the skeletal muscle molecular clock machinery in rats with stroke and determined the relationship of these changes with exercise-induced improvements in skeletal muscle health. Materials and methods: Overall, 168 Sprague-Dawley rats were included in this study. We established an ischemic stroke rat model of sarcopenia. Finally, 144 rats were randomly allocated to four groups (36 per group): normal, sham, middle cerebral artery occlusion, and training. Neurological scores, rotating rod test, body weight, muscle circumference, wet weight, and hematoxylin-eosin staining were assessed. Twenty-four rats were used for transcriptome sequencing. Gene and protein expressions of skeletal muscles, such as brain muscle arnt-like 1, period 1, and period 2, were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays. Results: Neurological function scores and rotating rod test results improved after treadmill training. Nine differentially expressed genes were identified by comparing the sham group with the hemiplegic side of the model group. Seventeen differentially expressed genes were identified between the hemiplegic and non-hemiplegic sides. BMAL1, PER1, and PER2 mRNA levels increased on both sides after treadmill training. BMAL1 expression increased, and PER1 expression decreased on both sides, whereas PER2 expression decreased on the hemiplegic side but increased on the non-hemiplegic side. Conclusion: Treadmill training can mitigate muscle loss and regulate skeletal muscle clock gene expression following ischemic stroke. Exercise affects the hemiplegic side and has a positive regulatory effect on the non-hemiplegic side.
RESUMEN
For understanding the mechanical performance and strain energy evolution mechanism of thick hard roof sandstone samples, a sequence of uniaxial compression trials with acoustic emission (AE) monitoring were carried out. The results indicate: (1) The stress-strain curve of the thick hard roof sandstone specimens exhibits distinct stage characteristics. Based on the evolvement of instantaneous axial stiffness, it is separated into Fracture Closure Phase, Elastic Deformation Phase, Steady Fracture Expansion Phase, Unsteady Fracture Expansion Phase, and Post-Peak Phase. (2) The AE energy and cumulative count curves of the thick hard roof sandstone specimens also exhibit significant stage characteristics and can be mutually corroborated with the stage division of the stress-strain curve. (3) Based on the energy conservation principle, the evolution of strain energy density in the thick hard roof sandstone specimens under uniaxial compression loading was analyzed, and plastic strain energy increment was employed to study the stage characteristics of strain energy dissipation. (4) A damage constitutive model for the thick hard roof sandstone specimens was constructed, considering the characteristics of strain energy dissipation. This model effectively describes the stress-strain relationship among the samples, which undergo strain hardening, strain softening, and sudden destruction.
RESUMEN
High fecundity is a common characteristic of insect pests which increases the difficulty of population control. Serine/threonine kinase Akt is an indispensable component of the insulin signaling pathway. Silencing of LsAkt severely hinders reproduction in Lasioderma serricorne, a stored product insect pest. However, the post-transcriptional pathway of LsAkt in L. serricorne remains unknown. This study identified 2 binding sites of miR-9c-5p and novel-mir50 in the coding sequences of LsAkt. The expression profiles of 2 microRNAs (miRNAs) and LsAkt displayed an opposite pattern during the adult stages. Luciferase reporter assay showed that novel-mir50 and miR-9c-5p could downregulate the expression of LsAkt. Overexpression of miR-9c-5p and novel-mir50 by injection of mimics inhibited the expression of LsAkt and reduced oviposition, decreased egg hatchability, and blocked ovarian development. It also decreased the expression of genes involved in ovarian development (LsVg and LsVgR) and the nutritional signaling pathway (LsTOR, LsS6K, and Ls4EBP), and reduced the phosphorylation of Akt. Conversely, injection of miR-9c-5p and novel-mir50 inhibitors induced the expressions of LsAkt, LsVg, LsVgR, LsTOR, LsS6K, and Ls4EBP, enhanced Akt phosphorylation level, and accelerated ovarian development. Injection of bovine insulin downregulated the expression of miR-9c-5p and novel-mir50 and upregulated the LsAkt expression. It also rescued the reproductive development defects associated with miR-9c-5p/novel-mir50 overexpression, forming a positive regulatory loop of insulin signaling. These results indicate that miR-9c-5p/novel-mir50 regulates the female reproduction of L. serricorne by targeting Akt in response to insulin signaling. The data also demonstrate the effects of the insulin/miRNA/Akt regulatory axis in insect reproduction.
Asunto(s)
MicroARNs , Proteínas Proto-Oncogénicas c-akt , Animales , Femenino , Bovinos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , MicroARNs/genética , MicroARNs/metabolismo , Insulina , ReproducciónRESUMEN
The generation of mature and healthy oocytes is the most critical event in the entire female reproductive process, and the mechanisms regulating this process remain to be studied. Here, we demonstrate that Smith-like (LSM) family member 14B (LSM14B) regulates oocyte maturation, and the loss of LSM14B in mouse ovaries leads to abnormal oocyte MII arrest and female infertility. Next, we find the aberrant transcriptional activation, indicated by abnormal non-surrounded nucleolus and surrounded nucleolus oocyte proportions, and abnormal chromosome assembly and segregation in Lsm14b-deficient mouse oocytes. The global transcriptome analysis suggests that many transcripts involved in cytoplasmic processing body (P-body) function are altered in Lsm14b-deficient mouse oocytes. Deletion of Lsm14b results in the expression and/or localization changes of P-body components (such as LSM14A, DCP1A, and 4E-T). Notably, DDX6, a key component of the P-body, is downregulated and accumulates in the nuclei in Lsm14b-deficient mouse oocytes. Taken together, our data suggest that LSM14B links mouse oocyte maturation to female fertility through the regulation of the P-body.
Asunto(s)
Oogénesis , Cuerpos de Procesamiento , Animales , Femenino , Ratones , Oocitos/metabolismo , Oogénesis/genéticaRESUMEN
Introduction: This study sought to explore the immunogenicity of a booster dose of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in people living with human immunodeficiency virus (HIV) and identify the factors affecting the magnitude of anti-SARS-CoV-2 antibody levels. Materials and methods: A total of 34 people living with HIV (PLWH) and 34 healthy donors (HD) were administered a booster dose of the same SARS-CoV-2 vaccine. Anti-SARS-CoV-2 antibody and immunoglobulin G (IgG) levels were measured using the SARS-CoV-2 S protein neutralizing antibody Enzyme-Linked Immunosorbent Assay (ELISA) and 2019-nCov IgG Chemiluminescent Immunoassay Microparticles, respectively. Spearman correlation analysis was used to measure the correlation between laboratory markers and neutralizing antibody and IgG levels. Peripheral blood mononuclear cells (PBMCs) were extracted from each subject using density gradient centrifugation and the numbers of memory T and T follicular helper (Tfh) cells were determined using flow cytometry. Results: PLWH had a marked reduction in CD4 and B cell levels that was accompanied by a lower CD4/CD8 T cell ratio. However, those who received a supplementary dose of inactivated SARS-CoV-2 vaccines exhibited antibody positivity rates that were analogous to levels previously observed. The booster vaccine led to a reduction in IgG and neutralizing antibody levels and the amplitude of this decline was substantially higher in the PLWH than HD group. Correlation analyses revealed a strong correlation between neutralizing antibody levels and the count and proportion of CD4 cells. Anti-SARS-CoV-2 IgG antibody levels followed a similar trend. The expression of memory T and Tfh cells was considerably lower in the PLWH than in the HD group. Discussion: PLWH had an attenuated immune response to a third (booster) administration of an inactivated SARS-CoV-2 vaccine, as shown by lower neutralizing antibody and IgG levels. This could be attributed to the reduced responsiveness of CD4 cells, particularly memory T and cTfh subsets. CD4 and cTfh cells may serve as pivotal markers of enduring and protective antibody levels. Vaccination dose recalibration may be critical for HIV-positive individuals, particularly those with a lower proportion of CD4 and Tfh cells.
Asunto(s)
COVID-19 , Seropositividad para VIH , Humanos , Vacunas contra la COVID-19 , VIH , Células T Auxiliares Foliculares , Leucocitos Mononucleares , COVID-19/prevención & control , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Inmunoglobulina GRESUMEN
Idiopathic fertility disorders are associated with mutations in various genes. Here, we report that coiled-coil glutamate-rich protein 1 (CCER1), a germline-specific and intrinsically disordered protein (IDP), mediates postmeiotic spermatid differentiation. In contrast, CCER1 deficiency results in defective sperm chromatin compaction and infertility in mice. CCER1 increases transition protein (Tnp1/2) and protamine (Prm1/2) transcription and mediates multiple histone epigenetic modifications during the histone-to-protamine (HTP) transition. Immiscible with heterochromatin in the nucleus, CCER1 self-assembles into a polymer droplet and forms a liquid-liquid phase-separated condensate in the nucleus. Notably, we identified loss-of-function (LoF) variants of human CCER1 (hCCER1) in five patients with nonobstructive azoospermia (NOA) that were absent in 2713 fertile controls. The mutants led to premature termination or frameshift in CCER1 translation, and disrupted condensates in vitro. In conclusion, we propose that nuclear CCER1 is a phase-separated condensate that links histone epigenetic modifications, HTP transitions, chromatin condensation, and male fertility.
Asunto(s)
Histonas , Infertilidad Masculina , Masculino , Humanos , Ratones , Animales , Histonas/genética , Histonas/metabolismo , Protaminas/genética , Protaminas/metabolismo , Semen/metabolismo , Cromatina/metabolismo , Espermatozoides/metabolismo , Espermatogénesis/genética , Fertilidad/genética , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismoRESUMEN
Ischemic stroke is a leading cause of death and disability in the world. At present, reperfusion therapy and neuroprotective therapy, as guidelines for identifying effective and adjuvant treatment methods, are limited by treatment time windows, drug bioavailability, and side effects. Nanomaterial-based drug delivery systems have the characteristics of extending half-life, increasing bioavailability, targeting drug delivery, controllable drug release, and low toxicity, thus being used in the treatment of ischemic stroke to increase the therapeutic effects of drugs. Therefore, this review provides a comprehensive overview of nanomaterial-based drug delivery systems from nanocarriers, targeting ligands and stimulus factors of drug release, aiming to find the best combination of nanomaterial-based drug delivery systems for ischemic stroke. Finally, future research areas on nanomaterial-based drug delivery systems in ischemic stroke and the implications of the current knowledge for the development of novel treatment for ischemic stroke were identified.
RESUMEN
Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-ß peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear. Methods: Depressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-δ). Further behavioral studies investigated the role of Tau N368-PPAR-δ interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS. Results: We found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-δ, repressing PPAR-δ-mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-δ. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-δ effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice. Conclusion: These results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-δ, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer's disease.
RESUMEN
Sepsis is a systemic inflammatory response syndrome caused by an infection progressing to sepsis-associated organ failure (such as lung injury). Our previous review revealed that Astragaloside IV (ASI-IV), one of the primary bioactive ingredients in Astragalus membranaceus (Fisch) Bge (Huang-Qi), had been shown to exert anti-inflammatory and immunomodulatory effects. Nevertheless, it is still unclear whether ASI-IV could attenuate septic lung injury via activating regulatory T-cells (Tregs). This study was designed to evaluate the therapeutic potential of ASI-IV on sepsis-induced lung injury and to further explore its underlying mechanism. In the murine models of cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) induced sepsis, ASI-IV can markedly improve the survival rate and reduce inflammatory lung injury, protect mice against exacerbated inflammatory responses by decreasing myeloid cell infiltration and down-regulating IL-6 and TNF-α in lung tissue. Meanwhile, Treg cell-related gene expression, including Foxp3 and IL-10, significantly increased after ASI-IV treatment. Furthermore, ASI-IV notably promoted the differentiation of naïve CD4+ T cells into T regulatory cells without obviously affecting Th1 and Th17 differentiation. Our results indicated that ASI-IV could attenuate septic lung injury by promoting Treg cell expansion and inhibiting inflammatory responses. It represents a promising agent for the treatment of sepsis.