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1.
Pain Ther ; 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38896199

RESUMO

INTRODUCTION: There is no approved effective drug for diabetic peripheral neuropathic pain (DPNP) in China. Gabapentinoids including mirogabalin have shown promise, although data in Chinese patients are scarce. METHODS: This phase 3, multicenter, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of mirogabalin for treating DPNP in China. Mirogabalin was administered at 5 mg twice daily for the first week and uptitrated to 15 mg twice daily for a total duration of 14 weeks. The primary efficacy endpoint was the change from baseline in weekly average daily pain score (ADPS) at week 14; secondary endpoints included the ADPS responder rate, Short-Form McGill Pain Questionnaire visual analogue scale score, patient global impression of change (PGIC), average daily sleep interference score (ADSIS), EuroQol 5-dimensions 5-levels (EQ-5D-5L), and incidence of treatment-emergent adverse events (TEAEs). RESULTS: Of 393 patients (mirogabalin, n = 196; placebo n = 197), the mean age was 58.2 years (mirogabalin, 58.7 years; placebo, 57.7 years) and 54.2% were male (mirogabalin, 56.1%; placebo, 52.3%). Mirogabalin elicited a greater change from baseline in the weekly ADPS vs. placebo at week 14: least-squares mean difference (95% confidence interval) vs. placebo - 0.39 (- 0.74, - 0.04), p = 0.0301. PGIC, ADSIS, and EQ-5D-5L data reflected significantly better improvements for patients receiving mirogabalin vs. placebo. The incidence of TEAEs was 75.0% and 75.1% in the mirogabalin and placebo groups, respectively. Most TEAEs were mild or moderate, and the incidence of TEAEs leading to treatment discontinuation was 2.6% in the mirogabalin group and 1.5% in the placebo group. CONCLUSIONS: Although the effect size of mirogabalin was reduced due to the placebo effect, mirogabalin is a safe and effective treatment option for Chinese patients with DPNP. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04094662.

2.
Syst Biol Reprod Med ; 70(1): 150-163, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38896558

RESUMO

The incidence of male infertility (MI) is rising annually. However, the lifestyle and occupational exposure factors contributing to MI remain incompletely understood. This study explored the effects of self-reported lifestyle and occupational exposure factors on semen quality. Among 1060 subjects invited to participate, 826 were eligible. The participants' general characteristics, lifestyle, and occupational exposure factors were collected immediately before or after semen evaluation through an online questionnaire. Initially, univariate analysis was used to investigate the relationship between the abovementioned factors and semen quality. The results indicated significant associations between low semen quality and various factors, including age, BMI, infertility type and duration, abstinence time, semen and sperm parameters, smoking, alcohol consumption, irregular sleep habits, and frequent exposure to high temperatures and chemicals at work (p < 0.05). Then, multivariate analysis was conducted to identify factors independently associated with low semen quality. Adjustment for relevant confounders was achieved by including factors with a p-value < 0.25 from univariate analyses as covariates in the binomial and ordered logistic regression models. The results suggested that alcohol consumption was a positive factor for sperm concentration (odds ratio [OR] = 0.60; 95% confidence interval [CI] = 0.36-0.99; p = 0.045). The groups with a BMI ≥ 24 and <28 kg/m2 showed a significant decrease in sperm progressive motility when compared to the reference group (BMI < 24 kg/m2) (OR = 0.63; 95% CI = 0.46-0.87, p = 0.005). In addition, the groups that drank green tea <1 time/week (OR = 1.52, 95% CI = 1.05-2.2) and 1-4 times/week (OR = 1.61, 95% CI = 1.02-2.54) exhibited significantly increased sperm DFI values compared with the group that drank green tea 5-7 times/week. In conclusion, these findings underscore the importance of maintaining a normal weight and regularly consuming green tea for men.


Assuntos
Infertilidade Masculina , Estilo de Vida , Exposição Ocupacional , Análise do Sêmen , Humanos , Masculino , Adulto , Exposição Ocupacional/efeitos adversos , Estudos Transversais , Infertilidade Masculina/etiologia , Infertilidade Masculina/epidemiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Fatores de Risco , Pessoa de Meia-Idade , Motilidade dos Espermatozoides , Contagem de Espermatozoides
3.
Nat Plants ; 10(6): 890-900, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38755277

RESUMO

Growing evidence indicates that plant community structure and traits have changed under climate warming, especially in cold or high-elevation regions. However, the impact of these warming-induced changes on ecosystem carbon sequestration remains unclear. Using a warming experiment on the high-elevation Qinghai-Tibetan Plateau, we found that warming not only increased plant species height but also altered species composition, collectively resulting in a taller plant community associated with increased net ecosystem productivity (NEP). Along a 1,500 km transect on the Plateau, taller plant community promoted NEP and soil carbon through associated chlorophyll content and other photosynthetic traits at the community level. Overall, plant community height as a dominant trait is associated with species composition and regulates ecosystem C sequestration in the high-elevation biome. This trait-based association provides new insights into predicting the direction, magnitude and sensitivity of ecosystem C fluxes in response to climate warming.


Assuntos
Sequestro de Carbono , Ecossistema , Aquecimento Global , Plantas/metabolismo , Fotossíntese , Mudança Climática , Altitude , Tibet , Carbono/metabolismo , Solo/química
4.
bioRxiv ; 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38712170

RESUMO

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here we identify C12orf29 as an atypical ATP-grasp enzyme that ligates RNA. Human C12orf29 and its homologs auto-adenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5'-phosphate and a 3'-hydroxyl. C12orf29 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Genetic depletion of c12orf29 in female mice alters global tRNA levels in brain. Furthermore, crystal structures of a C12orf29 homolog from Yasminevirus bound to nucleotides reveal a minimal and atypical RNA ligase fold with a unique active site architecture that participates in catalysis. Collectively, our results identify C12orf29 as an RNA ligase and suggest its involvement in tRNA biology.

5.
J Bioenerg Biomembr ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38743190

RESUMO

Septic cardiomyopathy is a severe cardiovascular disease with a poor prognosis. Previous studies have reported the involvement of ferroptosis in the pathogenesis of septic cardiomyopathy. SGLT2 inhibitors such as dapagliflozin have been demonstrated to improve ischemia-reperfusion injury by alleviating ferroptosis in cardiomyocyte. However, the role of dapagliflozin in sepsis remains unclear. Therefore, our study aims to investigate the therapeutic effects of dapagliflozin on LPS-induced septic cardiomyopathy. Our results indicate that dapagliflozin improved cardiac function in septic cardiomyopathy experimental mice. Mechanistically, dapagliflozin works by inhibiting the translation of key proteins involved in ferroptosis, such as GPX4, FTH1, and SLC7A11. It also reduces the transcription of lipid peroxidation-related mRNAs, including PTGS2 and ACSL4, as well as iron metabolism genes TFRC and HMOX1.

6.
BMC Microbiol ; 24(1): 169, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760705

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrinopathy in childbearing-age females which can cause many complications, such as diabetes, obesity, and dyslipidemia. The metabolic disorders in patients with PCOS were linked to gut microbial dysbiosis. However, the correlation between the gut microbial community and dyslipidemia in PCOS remains unillustrated. Our study elucidated the different gut microbiota in patients with PCOS and dyslipidemia (PCOS.D) compared to those with only PCOS and healthy women. RESULTS: In total, 18 patients with PCOS, 16 healthy females, and 18 patients with PCOS.D were enrolled. The 16 S rRNA sequencing in V3-V4 region was utilized for identifying the gut microbiota, which analyzes species annotation, community diversity, and community functions. Our results showed that the ß diversity of gut microbiota did not differ significantly among the three groups. Regarding gut microbiota dysbiosis, patients with PCOS showed a decreased abundance of Proteobacteria, and patients with PCOS.D showed an increased abundance of Bacteroidota compared to other groups. With respect to the gut microbial imbalance at genus level, the PCOS.D group showed a higher abundance of Clostridium_sensu_stricto_1 compared to other two groups. Furthermore, the abundances of Faecalibacterium and Holdemanella were lower in the PCOS.D than those in the PCOS group. Several genera, including Faecalibacterium and Holdemanella, were negatively correlated with the lipid profiles. Pseudomonas was negatively correlated with luteinizing hormone levels. Using PICRUSt analysis, the gut microbiota community functions suggested that certain metabolic pathways (e.g., amino acids, glycolysis, and lipid) were altered in PCOS.D patients as compared to those in PCOS patients. CONCLUSIONS: The gut microbiota characterizations in patients with PCOS.D differ from those in patients with PCOS and controls, and those might also be related to clinical parameters. This may have the potential to become an alternative therapy to regulate the clinical lipid levels of patients with PCOS in the future.


Assuntos
Bactérias , Disbiose , Dislipidemias , Microbioma Gastrointestinal , Síndrome do Ovário Policístico , RNA Ribossômico 16S , Humanos , Síndrome do Ovário Policístico/microbiologia , Feminino , Dislipidemias/microbiologia , Adulto , Disbiose/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , RNA Ribossômico 16S/genética , Adulto Jovem , Fezes/microbiologia
8.
Mol Neurobiol ; 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38649660

RESUMO

Light-based photo-stimulation has demonstrated promising effects on stem cell behavior, particularly in optimizing neurogenesis. However, the precise parameters for achieving optimal results, including the wavelengths, light intensity, radiating energy, and underlying mechanisms, remain incompletely understood. In this study, we focused on utilizing ultraviolet-C (UV-C) at a specific wavelength of 254 nm, with an ultra-low dose at intensity of 330 µW/cm2 and a total energy of 594 mJ/cm2 per day over a period of seven days, to stimulate the proliferation and differentiation of mouse neural stem cells (NSCs). The results revealed that the application of ultra-low-dose UV-C yielded the most significant effect in promoting differentiation when compared to mixed ultraviolet (UV) and ultraviolet-A (UV-A) radiation at equivalent exposure levels. The mechanism exploration elucidated the role of Presenilin 1 in mediating the activation of ß-catenin and Notch 1 by the UV-C treatment, both of which are key factors facilitating NSCs proliferation and differentiation. These findings introduce a novel approach employing ultra-low-dose UV-C for specifically enhancing NSC differentiation, as well as the underlying mechanism. It would contribute valuable insights into brain stimulation and neurogenesis modulation for various diseases, offering potential therapeutic avenues for further exploration.

10.
Heliyon ; 10(6): e28244, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38560689

RESUMO

Background: The immune microenvironment and oxidative stress of melanoma show significant heterogeneity, which affects tumor growth, invasion and treatment response. Single-cell and bulk RNA-seq data were used to explore the heterogeneity of the immune microenvironment and oxidative stress of melanoma. Methods: The R package Seurat facilitated the analysis of the single-cell dataset, while Harmony, another R package, was employed for batch effect correction. Cell types were classified using Uniform Manifold Approximation and Projection (UMAP). The Secreted Signaling algorithm from CellChatDB.human was applied to elucidate cell-to-cell communication patterns within the single-cell data. Consensus clustering analysis for the skin cutaneous melanoma (SKCM) samples was executed with the R package ConsensusClusterPlus. To quantify immune infiltrating cells, we utilized CIBERSORT, ESTIMATE, and TIMERxCell algorithms provided by the R package Immuno-Oncology Biological Research (IOBR). Single nucleotide variant (SNV) analysis was conducted using Maftools, an R package specifically designed for this purpose. Subsequently, the expression levels of PXDN and PAPSS2 genes were assessed in melanoma tissues compared to adjacent normal tissues. Furthermore, in vitro experiments were conducted to evaluate the proliferation and reactive oxygen species expression in melanoma cells following transfection with siRNA targeting PXDN and PAPSS2. Results: Malignant tumor cell populations were reclassified based on a comprehensive single-cell dataset analysis, which yielded six distinct tumor subsets. The specific marker genes identified for these subgroups were then used to interrogate the Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) cohort, derived from bulk RNA sequencing data, resulting in the delineation of two immune molecular subtypes. Notably, patients within the cluster2 (C2) subtype exhibited a significantly more favorable prognosis compared to those in the cluster1 (C1) subtype. An alignment of immune characteristics was observed between the C2 subtype and unique immune functional tumor cell subsets. Genes differentially expressed across these subtypes were subsequently leveraged to construct a predictive risk model. In vitro investigations further revealed elevated expression levels of PXDN and PAPSS2 in melanoma tissue samples. Functional assays indicated that modulation of PXDN and PAPSS2 expression could influence the production of reactive oxygen species (ROS) and the proliferative capacity of melanoma cells. Conclusion: The constructed six-gene signature can be used as an immune response and an oxidative stress marker to guide the clinical diagnosis and treatment of melanoma.

12.
Br J Pharmacol ; 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627101

RESUMO

BACKGROUND AND PURPOSE: Neuropathic pain, a debilitating condition with unmet medical needs, can be characterised as hyperexcitability of nociceptive neurons caused by dysfunction of ion channels. Voltage-gated potassium channels type 7 (Kv7), responsible for maintaining neuronal resting membrane potential and thus excitability, reside under tight control of G protein-coupled receptors (GPCRs). Calcium-sensing receptor (CaSR) is a GPCR that regulates the activity of numerous ion channels, but whether CaSR can control Kv7 channel function has been unexplored until now. EXPERIMENTAL APPROACH: Experiments were conducted in recombinant cell models, mouse dorsal root ganglia (DRG) neurons and human induced pluripotent stem cell (hiPSC)-derived nociceptive-like neurons using patch-clamp electrophysiology and molecular biology techniques. KEY RESULTS: Our results demonstrate that CaSR is expressed in recombinant cell models, hiPSC-derived nociceptive-like neurons and mouse DRG neurons, and its activation induced depolarisation via Kv7.2/7.3 channel inhibition. The CaSR-Kv7.2/7.3 channel crosslink was mediated via the Gi/o protein-adenylate cyclase-cyclicAMP-protein kinase A signalling cascade. Suppression of CaSR function demonstrated a potential to rescue hiPSC-derived nociceptive-like neurons from algogenic cocktail-induced hyperexcitability. CONCLUSION AND IMPLICATIONS: This study demonstrates that the CaSR-Kv7.2/7.3 channel crosslink, via a Gi/o protein signalling pathway, effectively regulates neuronal excitability, providing a feasible pharmacological target for neuronal hyperexcitability management in neuropathic pain.

13.
J Environ Manage ; 356: 120751, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38531131

RESUMO

Cost-effective treatment or even valorization of the bauxite residue (red mud) from the alumina industry is in demand to improve their environmental and economic liabilities. This study proposes a strategy that provides a near-complete conversion of bauxite residue to valuable products. The first step involves dilute acid leaching, which allowed the fractionation of raw residues into (1) an aqueous fraction rich in silica and aluminium and (2) a solid residue rich in iron, titanium and rare earth elements. For the proposed process, 91% of the original silicon, 67% of the aluminium, 78% of the scandium and 69% of the cerium were recovered. The initial cost evaluation suggested that this approach is profitable with a gross margin of 167 $US per tonne. This "Residue2Product" approach should be considered for large-scale practices as one of the most economical and sustainable solutions to this environmental and economic liability for the alumina industry.


Assuntos
Óxido de Alumínio , Alumínio , Óxido de Alumínio/química , Ferro , Titânio , Água
14.
Intensive Crit Care Nurs ; 83: 103665, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38471401

RESUMO

OBJECTIVE: To explore intensive care unit (ICU) nurses' perceptions of their adherence to pressure injury prevention clinical practice guideline and identify the perceived barriers and facilitators that influence evidence-based pressure injury prevention practices in Chinese tertiary hospitals. RESEARCH METHODOLOGY/DESIGN: This was a multi-site, quantitative, cross-sectional study. Data were collected using a self-report questionnaire with three sections: participant demographic information, adherence to pressure injury prevention clinical practice guideline, and barriers to and facilitators of pressure injury prevention clinical practice guideline implementation. SETTING: Thirty-three adult ICUs in 16 tertiary general hospitals in 5 major cities in Liaoning Province, China. RESULTS: In total, 473 nurses responded to the survey. The mean score for adherence to pressure injury prevention clinical practice guideline was 159.06 ± 20.65, with 65.3 % reporting good adherence. Multiple stepwise regression analysis indicated that smaller ICU size (ß = -0.114, p = 0.012) and having participated in training on pressure injury prevention clinical practice guideline (ß = 0.149, p = 0.001) were statistically significantly associated with better adherence. ICU nurses identified the low priority given to pressure injury prevention as the top barrier. The top three facilitators were awareness of evidence-based practice, the current documentation format for pressure injury risk/nursing interventions, and leadership support. CONCLUSION: ICU nurses' adherence to pressure injury prevention clinical practice guideline was satisfactory, and they reported low-to-moderate barriers and moderate facilitators. IMPLICATIONS FOR CLINICAL PRACTICE: Participating in training on pressure injury prevention clinical practice guideline was a predictor of ICU nurses' adherence. Therefore, it is highly recommended that healthcare organisations consider providing training to nurses and address the barriers identified to improve nurses' adherence to evidence-based pressure injury prevention guidelines.


Assuntos
Enfermagem de Cuidados Críticos , Fidelidade a Diretrizes , Unidades de Terapia Intensiva , Úlcera por Pressão , Humanos , Estudos Transversais , Úlcera por Pressão/prevenção & controle , Úlcera por Pressão/enfermagem , Fidelidade a Diretrizes/estatística & dados numéricos , Fidelidade a Diretrizes/normas , Feminino , Masculino , Adulto , Inquéritos e Questionários , China , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Pessoa de Meia-Idade , Enfermagem de Cuidados Críticos/normas , Enfermagem de Cuidados Críticos/métodos , Enfermagem de Cuidados Críticos/estatística & dados numéricos , Enfermeiras e Enfermeiros/estatística & dados numéricos , Enfermeiras e Enfermeiros/psicologia , Enfermeiras e Enfermeiros/normas , Guias de Prática Clínica como Assunto , Prática Clínica Baseada em Evidências/métodos
15.
Pan Afr Med J ; 47: 20, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38524104

RESUMO

In this case report, we will discuss a 74-year-old female who presented with a chief complaint of abdominal pain, bloating, anorexia, and nausea for four days which preceded after catheter ablation and anhydrous ethanol infusion vein of Marshall (VOM) one month prior. She was admitted and treated as a general patient in the general ward. After hospital admission, a pericardiocentesis was guided by B-scan ultrasonography, resulting in the extraction of 20ml of pericardial effusion, followed by catheterization for drainage. The key takeaway in this report is that anhydrous ethanol infusion VOM may not always be without risks. Hence, during the procedure, it is imperative to carefully administer the appropriate volume of anhydrous ethanol into the VOM to prevent vessel damage and associated complications.


Assuntos
Fibrilação Atrial , Ablação por Cateter , Pericardite , Feminino , Humanos , Idoso , Fibrilação Atrial/cirurgia , Etanol/efeitos adversos , Infusões Intravenosas , Vasos Coronários/cirurgia , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos
16.
Biomedicines ; 12(3)2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38540295

RESUMO

Spinal cord injury (SCI), a prevalent and disabling neurological condition, prompts a growing interest in stem cell therapy as a promising avenue for treatment. Dental-derived stem cells, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), stem cells from the apical papilla (SCAP), dental follicle stem cells (DFSCs), are of interest due to their accessibility, minimally invasive extraction, and robust differentiating capabilities. Research indicates their potential to differentiate into neural cells and promote SCI repair in animal models at both tissue and functional levels. This review explores the potential applications of dental-derived stem cells in SCI neural repair, covering stem cell transplantation, conditioned culture medium injection, bioengineered delivery systems, exosomes, extracellular vesicle treatments, and combined therapies. Assessing the clinical effectiveness of dental-derived stem cells in the treatment of SCI, further research is necessary. This includes investigating potential biological mechanisms and conducting Large-animal studies and clinical trials. It is also important to undertake more comprehensive comparisons, optimize the selection of dental-derived stem cell types, and implement a functionalized delivery system. These efforts will enhance the therapeutic potential of dental-derived stem cells for repairing SCI.

17.
MedComm (2020) ; 5(4): e514, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38495123

RESUMO

Electrical brain stimulation (EBS) has gained popularity for laboratory and clinical applications. However, comprehensive characterization of cellular diversity and gene expression changes induced by EBS remains limited, particularly with respect to specific brain regions and stimulation sites. Here, we presented the initial single-nucleus RNA sequencing profiles of rat cortex, hippocampus, and thalamus subjected to intracranial alternating current stimulation (iACS) at 40 Hz. The results demonstrated an increased number of neurons in all three regions in response to iACS. Interestingly, less than 0.1% of host gene expression in neurons was significantly altered by iACS. In addition, we identified Rgs9, a known negative regulator of dopaminergic signaling, as a unique downregulated gene in neurons. Unilateral iACS produced a more focused local effect in attenuating the proportion of Rgs9+ neurons in the ipsilateral compared to bilateral iACS treatment. The results suggested that unilateral iACS at 40 Hz was an efficient approach to increase the number of neurons and downregulate Rgs9 gene expression without affecting other cell types or genes in the brain. Our study presented the direct evidence that EBS could boost cerebral neurogenesis and enhance neuronal sensitization to dopaminergic drugs and agonists, through its downregulatory effect on Rgs9 in neurons.

18.
Andrology ; 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38385883

RESUMO

OBJECTIVES: In male mice, adgb-knockout has been reported to cause male infertility with spermatogenesis defects involving flagella and acrosome. However, this remains unclear for humans. MATERIALS AND METHODS: Sequencing studies were conducted in a research hospital on samples from three unrelated infertile men with severe asthenoteratozoospermia from Han Chinese families. Data were collected through rigorous in silico analysis. Sanger sequencing were performed to identify pathogenic mutations. Sperm cells from patients were characterized using electron microscopy and used to verify the pathogenicity of the genetic factors through functional assays. Intracytoplasmic sperm injections (ICSI) assays were performed in ADGB-affected males. MAIN RESULTS: Herein, in a cohort of 105 Han Chinese men with idiopathic asthenoteratozoospermia, we reported the identification of bi-allelic deleterious variants of ADGB in three infertile men from unrelated families using whole-exome sequencing. We found one homozygous frameshift ADGB variant (NM_024694.4: c.2801_2802del:p.K934Rfs*33), one homozygous missense ADGB variant (NM_024694.4: c.C3167T:p.T1056I), and one compound heterozygous ADGB variant (NM_024694.4: c.C3167T:p.T1056I; c.C3197T:p.A1066V). These variants were rare in general population and were predicted to be damaging by multiple bioinformatics tools. Further, the spermatozoa from patients harboring ADGB variants showed multiple acrosome and flagellum malformations under light and electron microscopy. Functional assays revealed the structural defects associated with dysregulation of ADGB and multiple spermatogenesis proteins. Notably, the fertilization success via ICSI treatment in all three patients, as well as the normal expression of PLCζ but CaM deficiency in the spermatozoa, suggesting that ICSI other than in vitro fertilization (IVF) is an optimal treatment for ADGB-deficient patients. DISCUSSION AND CONCLUSION: Our findings provide new information for the molecular diagnosis of asthenoteratozoospermia and valuable reference for personalized genetic counselling and clinical treatment for these patients. The underlying risk of IVF failure behind sperm defects was highlighted.

19.
Redox Biol ; 70: 103057, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38325196

RESUMO

Neuroinflammation and oxidative stress play a crucial role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease. The triggering receptor expressed on myeloid cells 2 (TREM2), highly expressed by microglia in the central nervous system (CNS), can modulate neuroinflammatory responses. Currently, there are no approved drugs specifically targeting TREM2 for CNS diseases. Aspidosperma alkaloids have shown potential as anti-inflammatory and neuroprotective agents. This study aimed to elucidate the potential therapeutic effect of Hecubine, a natural aspidosperma-type alkaloid, as a TREM2 activator in lipopolysaccharide (LPS)-stimulated neuroinflammation in in vitro and in vivo models. In this study, molecular docking and cellular thermal shift assay (CTSA) were employed to investigate the interaction between Hecubine and TREM2. Enzyme-linked immunosorbent assay (ELISA), quantitative PCR, immunofluorescence, Western blotting, and shRNA gene knockdown were used to assess the anti-neuroinflammatory and antioxidant effects of Hecubine in microglial cells and zebrafish. Our results revealed that Hecubine directly interacted with TREM2, leading to its activation. Knockdown of TREM2 mRNA expression significantly abolished the anti-inflammatory and antioxidant effects of Hecubine on LPS-stimulated proinflammatory mediators (NO, TNF-α, IL-6, and IL-1ß) and oxidative stress in microglia cells. Furthermore, Hecubine upregulated Nrf2 expression levels while downregulating TLR4 signaling expression levels both in vivo and in vitro. Silencing TREM2 upregulated TLR4 and downregulated Nrf2 signaling pathways, mimicking the effect of Hecubine, further supporting TREM2 as the drug target by which Hecubine inhibits neuroinflammation. In conclusion, this is the first study to identify a small molecule, namely Hecubine directly targeting TREM2 to mediate anti-neuroinflammation and anti-oxidative effects, which serves as a potential therapeutic agent for the treatment of neural inflammation-associated CNS diseases.


Assuntos
Doença de Alzheimer , Aspidosperma , Animais , Lipopolissacarídeos/toxicidade , Aspidosperma/metabolismo , Doenças Neuroinflamatórias , Receptor 4 Toll-Like/metabolismo , Fator 2 Relacionado a NF-E2 , Antioxidantes/uso terapêutico , Simulação de Acoplamento Molecular , Peixe-Zebra/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/genética , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doença de Alzheimer/metabolismo
20.
Artigo em Inglês | MEDLINE | ID: mdl-38393838

RESUMO

In recent years, data-driven soft sensor modeling methods have been widely used in industrial production, chemistry, and biochemical. In industrial processes, the sampling rates of quality variables are always lower than those of process variables. Meanwhile, the sampling rates among quality variables are also different. However, few multi-input multi-output (MIMO) sensors take this temporal factor into consideration. To solve this problem, a deep-learning (DL) model based on a multitemporal channels convolutional neural network (MC-CNN) is proposed. In the MC-CNN, the network consists of two parts: the shared network used to extract the temporal feature and the parallel prediction network used to predict each quality variable. The modified BP algorithm makes the blank values generated at unsampled moments not participate in the backpropagation (BP) process during training. By predicting multiple quality variables of two industrial cases, the effectiveness of the proposed method is verified.

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