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BACKGROUND AND OBJECTIVE: Endometriosis and adenomyosis are two common diseases that impair women's health, and dienogest is one of the pharmacologic treatments which is the first-line therapeutic option for patients with pelvic pain and individuals who have no desire for immediate pregnancy. The goal of this study was to summarize the current evidence of adverse events associated with dienogest as well as the prevalence of these adverse events during treatment with dienogest. METHODS: Several databases (PubMed, Embase, Cochrane Central and Clinicaltrials.gov, etc.) and the US FDA Adverse Event Reporting System (FAERS) Public Dashboard were searched on May 31, 2023, using the topic words alongside free words of dienogest and "adverse reaction". Studies were incorporated into this research if they reported or assessed safety issues or adverse reactions of dienogest during the period of endometriosis treatment or adenomyosis therapy. The extracted information comprised trial design, dienogest and control group demographics, as well as reported side effects. RESULTS: This systematic review comprehended 39 publications in total. The mean age of patients in the included studies was 34.43 years. The follow-up duration varied from 3 to 60 months. Most adverse reactions were common and not serious, and the most common adverse reactions during dienogest medication were abnormal uterine bleeding (55%, 95% CI 37-73%), amenorrhea (17%, 95% CI 2-42%) and swelling (13%, 95% CI 3-28%). Uncommon adverse reactions included dysmenorrhea (0.2%, n = 1), dyspepsia (0.4%, n = 1), and (lower) abdominal pain (1%, 95% CI 0-3%), urticaria (1%, 95% CI 0-3%) and peritonitis (1%, n = 1). Serious adverse reactions including decreased lumbar spine Bone Mineral Density (BMD), depression, peritonitis and so on have been reported. Heterogeneity assessment revealed that patient number and study design are influencing factors to adverse reaction prevalence. Moreover, abdominal pain, diarrhea, nausea and vomiting, back pain and anemia are side effects reported both in the FAERS database and in the systematic review. CONCLUSIONS: Dienogest's most frequent side effects were not severe. Dienogest is generally safe for treating endometriosis and adenomyosis. Nevertheless, people should be aware of serious adverse reactions, such as decreased lumbar spine BMD and hemorrhagic shock.
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Teorema de Bayes , Endometriosis , Nandrolona , Humanos , Nandrolona/análogos & derivados , Nandrolona/efectos adversos , Nandrolona/uso terapéutico , Femenino , Endometriosis/tratamiento farmacológico , Adenomiosis/tratamiento farmacológico , Antagonistas de Hormonas/efectos adversos , Antagonistas de Hormonas/uso terapéuticoRESUMEN
Adopting a non-covalent co-assembly strategy shows great potential in loading drugs efficiently and safely in drug delivery systems. However, finding an efficient method for developing high strength gels with thixotropic characteristics is still challenging. In this work, by hybridizing the low molecular weight gelator fluorenylmethyloxycarbonyl-phenylalanine (Fmoc-F) (first single network, 1st SN) and alginate (second single network, 2nd SN) into a dual network (DN) gel, gels with high strength as well as thixotropy were prepared efficiently. The DN gels showed high strength (103 Pa in SN gels and 105 Pa in DN gels) and thixotropic characteristics (yield strain <25%; recovery ratio >85% within 100 seconds). The application performance was verified by loading doxorubicin (DOX), showing better encapsulation capacity (77.06% in 1st SN, 59.11% in 2nd SN and 96.71% in DN) and sustained release performance (lasting one week under physiological conditions) than single network gels. Experimental and DFT results allowed the elaboration of the specific non-covalent co-assembly mechanism for DN gel formation and DOX loading. The DN gels were formed by co-assembly driven by H-bond and π-π stacking interactions and then strengthened by Ca2+-coupling. Most DOX molecules co-assembled with Fmoc-F and alginate through π-π stacking and H-bond interactions (DOX-I), with a few free DOX molecules (DOX-II) left. Proven by the release dynamics test, DOX was released through a diffusion-erosion process, in an order of DOX-I first and then DOX-II. This work suggests that non-covalent co-assembly is a useful technique for effective material strengthening and drug delivery.
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Alginatos , Doxorrubicina , Liberación de Fármacos , Geles , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Geles/química , Alginatos/química , Preparaciones de Acción Retardada/química , Portadores de Fármacos/química , Fluorenos/química , Fenilalanina/químicaRESUMEN
The malignancy of breast cancer poses a global challenge, with existing treatments often falling short of desired efficacy. Extensive research has underscored the effectiveness of targeting the metabolism of nicotinamide adenine dinucleotide (NAD), a pivotal molecule crucial for cancer cell survival and growth, as a promising anticancer strategy. Within mammalian cells, sustaining optimal NAD concentrations relies on two key enzymes, namely nicotinamide phosphoribosyltransferase (NAMPT) and poly(ADP-ribose) polymer 1 (PARP1). Recent studies have accentuated the potential benefits of combining NAMPT inhibitors and PARP1 inhibitors to enhance therapeutic outcomes, particularly in breast cancer. In this study, we designed and synthesized eleven novel NAMPT/PARP1 dual-target inhibitors. Among them, compound DDY02 exhibited acceptable inhibitory activities against both NAMPT and PARP1, with IC50 values of 0.01 and 0.05 µM, respectively. Moreover, in vitro evaluations revealed that treatment with DDY02 resulted in proliferation inhibition, NAD depletion, DNA damage, apoptosis, and migration inhibition in MDA-MB-468 cells. These results posit DDY02, by targeting NAD metabolism through inhibiting both NAMPT and PARP1, as a promising lead compound for the development of breast cancer therapy.
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Antineoplásicos , Neoplasias de la Mama , Proliferación Celular , NAD , Nicotinamida Fosforribosiltransferasa , Poli(ADP-Ribosa) Polimerasa-1 , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Nicotinamida Fosforribosiltransferasa/metabolismo , Humanos , NAD/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Femenino , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Diseño de Fármacos , Citocinas/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Simulación del Acoplamiento MolecularRESUMEN
Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) contributes to the progression of CKD to renal failure. In order to improve the solubility, bioavailability, and targeting of tanshinone IIA (Tan IIA), a novel targeting material, aminoethyl anisamide-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphate ethanolamine (AEAA-PEG-DSPE, APD) modified Tan IIA liposomes (APD-Tan IIA-L) was constructed. An animal model of glomerulonephritis induced by doxorubicin in BALB/c mice was established. APD-Tan IIA-L significantly decreased blood urea nitrogen and serum creatinine (SCr), and the consequences of renal tissue oxidative stress indicators showed that APD-Tan IIA-L downregulated malondialdehyde, upregulated superoxide dismutase, catalase, and glutathione peroxidase. Masson's trichrome staining showed that the deposition of collagen in the APD-Tan IIA-L group decreased significantly. The pro-fibrotic factors (fibronectin, collagen I, TGF-ß1, and α-SMA) and epithelial-mesenchymal transition marker (N-cadherin) were significantly inhibited by APD-Tan IIA-L. By improving the microenvironment of fibrotic kidneys, APD-Tan IIA-L attenuated TGF-ß1-induced excessive proliferation of fibroblasts and alleviated oxidative stress damage to the kidney, providing a new strategy for the clinical treatment of renal fibrosis.
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Abietanos , Doxorrubicina , Fibrosis , Glomerulonefritis , Riñón , Liposomas , Ratones Endogámicos BALB C , Animales , Ratones , Liposomas/química , Abietanos/farmacología , Abietanos/química , Fibrosis/tratamiento farmacológico , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Masculino , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/inducido químicamente , Glomerulonefritis/patología , Factor de Crecimiento Transformador beta1/metabolismo , Estrés Oxidativo/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Modelos Animales de Enfermedad , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/inducido químicamenteRESUMEN
The oral delivery of doxorubicin (DOX), an anti-cancer drug, encounters multiple hurdles such as limited gastrointestinal permeability, P-glycoprotein-mediated efflux, brief intestinal residence, and rapid degradation. This study introduced a novel approach utilizing hyaluronic acid (HA)-grafted fatty acid monoglycerides (HGD) to encapsulate DOX, forming HGD-DOX nanoparticles, aimed at enhancing its oral bioavailability. Drug encapsulated by HGD provided several advantages, including extended drug retention in the gastrointestinal tract, controlled release kinetics, and promotion of lymphatic absorption in the intestine. Additionally, HGD-DOX nanoparticles could specifically target CD44 receptors, potentially increasing therapeutic efficacy. The uptake mechanism of HGD-DOX nanoparticles primarily involved clathrin-mediated, caveolin-mediated and macropinocytosis endocytosis. Pharmacokinetic analysis further revealed that HGD significantly prolonged the in vivo residence time of DOX. In vivo imaging and pharmacodynamic studies indicated that HGD possessed tumor-targeting capabilities and exhibited a significant inhibitory effect on tumor growth, while maintaining an acceptable safety profile. Collectively, these findings position HGD-DOX nanoparticles as a promising strategy to boost the oral bioavailability of DOX, offering a potential avenue for improved cancer treatment.
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Doxorrubicina , Receptores de Hialuranos , Ácido Hialurónico , Nanopartículas , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Ácido Hialurónico/química , Animales , Nanopartículas/química , Receptores de Hialuranos/metabolismo , Humanos , Administración Oral , Ratones , Portadores de Fármacos/química , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Breast cancer, the most prevalent malignant tumor among women globally, is significantly influenced by the Wnt/ß-catenin signaling pathway, which plays a crucial role in its initiation and progression. While conventional chemotherapy, the standard clinical treatment, suffers from significant drawbacks like severe side effects, high toxicity, and limited prognostic efficacy, Traditional Chinese Medicine (TCM) provides a promising alternative. TCM employs a multi-targeted therapeutic approach, which results in fewer side effects and offers a high potential for effective treatment. This paper presents a detailed analysis of the therapeutic impacts of TCM on various subtypes of breast cancer, focusing on its interaction with the Wnt/ß-catenin signaling pathway. Additionally, it explores the effectiveness of both monomeric and compound forms of TCM in the management of breast cancer. We also discuss the potential of establishing biomarkers for breast cancer treatment based on key proteins within the Wnt/ß-catenin signaling pathway. Our aim is to offer new insights into the prevention and treatment of breast cancer and to contribute to the standardization of TCM.
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This study introduces a groundbreaking optical coherence tomography (OCT) imaging system dedicated for high-throughput screening applications using ex vivo tissue culture. Leveraging OCT's non-invasive, high-resolution capabilities, the system is equipped with a custom-designed motorized platform and tissue detection ability for automated, successive imaging across samples. Transformer-based deep learning segmentation algorithms further ensure robust, consistent, and efficient readouts meeting the standards for screening assays. Validated using retinal explant cultures from a mouse model of retinal degeneration, the system provides robust, rapid, reliable, unbiased, and comprehensive readouts of tissue response to treatments. This fully automated OCT-based system marks a significant advancement in tissue screening, promising to transform drug discovery, as well as other relevant research fields.
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Polycystic ovary syndrome (PCOS) is a condition resulting from the interaction between environmental factors and hereditary components, profoundly affecting offspring development. Although the etiology of this disease remains unclear, aberrant in utero androgen exposure is considered one of the pivotal pathogenic factors. Herein, we demonstrate the intergenerational inheritance of PCOS-like phenotypes in F2 female offspring through F1 males caused by maternal testosterone exposure in F0 mice. We found impaired serum hormone expression and reproductive system development in prenatal testosterone-treated F1 male and F2 female mice (PTF1 and PTF2). In addition, downregulated N6-methyladenosine (m6A) methyltransferase and binding proteins induced mRNA hypomethylation in the PTF1 testis, including frizzled-6 (Fzd6). In the PTF2 ovary, decreased FZD6 protein expression inhibited the mammalian target of rapamycin (mTOR) signaling pathway and activated Forkhead box O3 (FoxO3) phosphorylation, which led to impaired follicular development. These data indicate that epigenetic modification of the mTOR signaling pathway could be involved in the intergenerational inheritance of maternal testosterone exposure-induced impairments in the PTF2 ovary through male PTF1 mice.
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Herencia Paterna , Efectos Tardíos de la Exposición Prenatal , Testosterona , Animales , Femenino , Masculino , Ratones , Efectos Tardíos de la Exposición Prenatal/genética , Embarazo , Testosterona/sangre , Herencia Paterna/genética , Exposición Materna/efectos adversos , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/inducido químicamente , Epigénesis Genética , Andrógenos/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ovario/metabolismo , Ovario/efectos de los fármacos , Testículo/metabolismo , Testículo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Metilación de ADN/efectos de los fármacos , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genéticaRESUMEN
BACKGROUND: Mammary gland development is a critical process in mammals, crucial for their reproductive success and offspring nourishment. However, the functional roles of key candidate genes associated with teat number, including ABCD4, VRTN, PROX2, and DLST, in this developmental process remain elusive. To address this gap in knowledge, we conducted an in-depth investigation into the dynamic expression patterns, functional implications, and regulatory networks of these candidate genes during mouse mammary gland development. RESULTS: In this study, the spatial and temporal patterns of key genes were characterized in mammary gland development. Using time-series single-cell data, we uncovered differences in the expression of A bcd4, Vrtn, Prox2, and Dlst in cell population of the mammary gland during embryonic and adult stages, while Vrtn was not detected in any cells. We found that only overexpression and knockdown of Abcd4 could inhibit proliferation and promote apoptosis of HC11 mammary epithelial cells, whereas Prox2 and Dlst had no significant effect on these cells. Using RNA-seq and qPCR, further analysis revealed that Abcd4 can induce widespread changes in the expression levels of genes involved in mammary gland development, such as Igfbp3, Ccl5, Tlr2, and Prlr, which were primarily associated with the MAPK, JAK-STAT, and PI3K-AKT pathways by functional enrichment. CONCLUSIONS: These findings revealed ABCD4 as a candidate gene pivotal for regulating mammary gland development and lactation during pregnancy by influencing PRLR expression.
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Transportadoras de Casetes de Unión a ATP , Glándulas Mamarias Animales , Animales , Femenino , Ratones , Apoptosis/genética , Proliferación Celular , Células Epiteliales/metabolismo , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Glándulas Mamarias Animales/crecimiento & desarrollo , Glándulas Mamarias Animales/metabolismo , Transducción de Señal , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismoRESUMEN
BACKGROUND: We compared the efficacy and safety of a modified cocktail for postoperative analgesia and early functional rehabilitation in patients undergoing total hip arthroplasty (THA). METHODS: Magnesium sulfate and sodium bicarbonate were added to a cocktail of ropivacaine, epinephrine, and dexamethasone. Primary outcome measures were visual analog scale (VAS) pain scores at various intervals after surgery, morphine consumption for rescue analgesia after surgery, and time to first rescue analgesia. Secondary outcomes were hip function after surgery, daily walking distance, quadriceps muscle strength, and the incidence of postoperative adverse reactions. RESULTS: Morphine consumption was significantly lower in the modified cocktail group than in the control group in the first 24 hours after surgery (6.2 ± 6.0 versus 14.2 ± 6.4 mg, P < .001), as was total morphine consumption (10.0 ± 8.6 versus 19.2 ± 10.1 mg, P < .001). The duration of the first rescue analgesia was significantly prolonged (23.7 ± 10.3 versus 11.9 ± 5.8 mg, P < .001). Morphine consumption was also reduced in the magnesium sulfate and sodium bicarbonate groups over a 24-hour period compared to the control group (P < .001). The modified cocktail group had significantly lower resting VAS pain scores than the control group within 24 hours after surgery (P < .050). The VAS pain scores during movement within 12 hours after surgery were also lower (P < .050). The experimental groups showed better hip range of motion (P < .050) and longer walking distance (P < .050) on the first postoperative day, and levels of inflammatory markers were significantly reduced. The incidence of postoperative adverse reactions was similar among the 4 groups. CONCLUSIONS: The modified cocktail with a new adjuvant can prolong the duration of postoperative analgesia, reduce the dosage of rescue analgesics, and accelerate early postoperative functional recovery in patients undergoing THA.
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Musk secreted by male forest musk deer (Moschus berezovskii) musk glands is an invaluable component of medicine and perfume. Musk secretion depends on musk gland maturation; however, the mechanism of its development remains elusive. Herein, using single cell multiome ATAC + gene expression coupled with several bioinformatic analyses, a dynamic transcriptional cell atlas of musk gland development was revealed, and key genes and transcription factors affecting its development were determined. Twelve cell types, including two different types of acinar cells (Clusters 0 and 10) were identified. Single-nucleus RNA and single-nucleus ATAC sequencing analyses revealed that seven core target genes associated with musk secretion (Hsd17b2, Acacb, Lss, Vapa, Aldh16a1, Aldh7a1, and Sqle) were regulated by 12 core transcription factors (FOXO1, CUX2, RORA, RUNX1, KLF6, MGA, NFIC, FOXO3, ETV5, NR3C1, HSF4, and MITF) during the development of Cluster 0 acinar cells. Kyoto Encyclopedia of Genes and Genomes enrichment showed significant changes in the pathways associated with musk secretion during acinar cell development. Gene set variation analysis also revealed that certain pathways associated with musk secretion were enriched in 6-year-old acinar cells. A gene co-expression network was constructed during acinar cell development to provide a precise understanding of the connections between transcription factors, genes, and pathways. Finally, intercellular communication analysis showed that intercellular communication is involved in musk gland development. This study provides crucial insights into the changes and key factors underlying musk gland development, which serve as valuable resources for studying musk secretion mechanisms and promoting the protection of this endangered species.
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Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood-brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin-1 (Lip) is proposed to alleviate the side effects. A well-designed macrocyclic carrier, glucose-modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke.
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Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos , Ferroptosis , Accidente Cerebrovascular Isquémico , Activador de Tejido Plasminógeno , Animales , Ferroptosis/efectos de los fármacos , Ratones , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Activador de Tejido Plasminógeno/farmacología , Activador de Tejido Plasminógeno/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Masculino , Quinoxalinas , Compuestos de EspiroRESUMEN
Squamous intraepithelial lesion of cervix (SIL) in human papillomavirus (HPV)-positive patient often undergoes a silent and long-course development, and most of them with high-grade transit to cervical squamous cell carcinoma (CSCC). The oxysterol 25-hydroxycholesterol (25-HC) is associated with HPV inhibition, autophagy and cholesterol synthesis, however, its function in this long process of SIL development remain unclear. In this study, we demonstrate that 25-HC generation is inhibited through HSIL-to-CSCC transition. The 25-HC activates ferritinophagy in the early stage of SIL, promoting the vulnerability of HSILs to ferroptosis. Therefore, maintaining 25-HC level is crucial for suppressing HSIL progression and holds promise for developing novel clinical therapies for CSCC.
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Actinidia arguta, the most widely distributed Actinidia species and the second cultivated species in the genus, can be distinguished from the currently cultivated Actinidia chinensis on the basis of its small and smooth fruit, rapid softening, and excellent cold tolerance. Adaptive evolution of tetraploid Actinidia species and the genetic basis of their important agronomic traits are still unclear. Here, we generated a chromosome-scale genome assembly of an autotetraploid male A. arguta accession. The genome assembly was 2.77 Gb in length with a contig N50 of 9.97 Mb and was anchored onto 116 pseudo-chromosomes. Resequencing and clustering of 101 geographically representative accessions showed that they could be divided into two geographic groups, Southern and Northern, which first diverged 12.9 million years ago. A. arguta underwent two prominent expansions and one demographic bottleneck from the mid-Pleistocene climate transition to the late Pleistocene. Population genomics studies using paleoclimate data enabled us to discern the evolution of the species' adaptation to different historical environments. Three genes (AaCEL1, AaPME1, and AaDOF1) related to flesh softening were identified by multi-omics analysis, and their ability to accelerate flesh softening was verified through transient expression assays. A set of genes that characteristically regulate sexual dimorphism located on the sex chromosome (Chr3) or autosomal chromosomes showed biased expression during stamen or carpel development. This chromosome-level assembly of the autotetraploid A. arguta genome and the genes related to important agronomic traits will facilitate future functional genomics research and improvement of A. arguta.
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Actinidia , Genoma de Planta , Tetraploidía , Actinidia/genética , Evolución Molecular , Adaptación Fisiológica/genética , Evolución BiológicaRESUMEN
OBJECTIVE: Preoperative anemia has been identified as a modifiable risk factor for multiple adverse outcomes. In real clinical practice, considering treatment of anemia would increase costs and delay surgery. Patients undergoing total hip arthroplasty (THA) with mild anemia are usually neglected and still underdiagnosed or inadequately treated. This study investigated the effects of preoperative borderline anemia and anemia intervention before THA on perioperative outcomes. METHODS: We screened 706 patients from those receiving THA at our hospital from January 2020 to January 2022, with 112 in the borderline anemia group and 594 in the non-anemia group. The cohort for this retrospective study was created by using propensity score matching (PSM) and subgroup analysis. The primary outcome was perioperative blood loss, while secondary outcomes were the rate of allogeneic blood transfusion and human serum albumin transfusion, perioperative laboratory indicators, postoperative length of stay, and complications. The independent sample t-test and the Mann-Whitney U-test were used to analyze continuous data, and the Pearson χ2 -test or the Fisher exact test was used to analyze categorical variables. RESULTS: After PSM, there was no significant difference in perioperative blood loss between patients in the borderline anemia group and the non-anemia group. The primary outcomes of hidden (p = 0.004) and total (p = 0.005) blood loss were significantly lower in the intervention group than in the control group. No statistical differences were found in allogeneic blood transfusion, human serum albumin transfusion, postoperative length of stay, or complications (p > 0.05). CONCLUSIONS: Anemia treatments for patients with borderline anemia before THA significantly reduced hidden blood loss and total blood loss in the perioperative period and decreased the drop of hemoglobin and hematocrit without increasing postoperative complications.
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Anemia , Artroplastia de Reemplazo de Cadera , Humanos , Estudios de Cohortes , Artroplastia de Reemplazo de Cadera/efectos adversos , Estudios Retrospectivos , Pérdida de Sangre Quirúrgica , Puntaje de Propensión , Resultado del Tratamiento , Anemia/terapia , Anemia/complicaciones , Complicaciones Posoperatorias/etiología , Albúmina Sérica HumanaRESUMEN
BACKGROUND: Many patients experience lower-extremity swelling following total knee arthroplasty (TKA), which impedes recovery. Diosmin is a semisynthetic flavonoid that is often utilized to treat swelling and pain caused by chronic venous insufficiency. We aimed to evaluate the efficacy and safety of diosmin in reducing lower-extremity swelling and pain as well as in improving functional outcomes following TKA. METHODS: This study was designed as a randomized, controlled multicenter trial and conducted in 13 university-affiliated tertiary hospitals. A total of 330 patients undergoing TKA were randomized to either receive or not receive diosmin postoperatively. The diosmin group received 0.9 g of diosmin twice per day for 14 consecutive days starting on the day after surgery, whereas the control group received neither diosmin nor a placebo postoperatively. The primary outcome was lower-extremity swelling 1, 2, 3, and 14 days postoperatively. The secondary outcomes were postoperative pain assessed with use of a visual analogue scale, Hospital for Special Surgery score, range of knee motion, levels of the inflammatory biomarkers C-reactive protein and interleukin-6, and complications. RESULTS: At all postoperative time points, diosmin was associated with significantly less swelling of the calf, thigh, and upper pole of the patella as well as with significantly lower pain scores during motion. However, no significant differences in postoperative pain scores at rest, Hospital for Special Surgery scores, range of motion, levels of inflammatory biomarkers, or complication rates were found between the diosmin and control groups. CONCLUSIONS: The use of diosmin after TKA reduced lower-extremity swelling and pain during motion and was not associated with an increased incidence of short-term complications involving the outcomes studied. However, further studies are needed to continue exploring the efficacy and safety of diosmin use in TKA. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.
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Artroplastia de Reemplazo de Rodilla , Diosmina , Humanos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Diosmina/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Dolor Postoperatorio/etiología , Muslo , Biomarcadores , Resultado del TratamientoRESUMEN
BACKGROUND: Epoxyeicosatrienoic acids (EETs), which exert multiple endogenous protective effects, are hydrolyzed into less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). However, commercial drugs related to EETs or sEH are not yet in clinical use. METHODS: Firstly, the plasma concentration of EETs and DHETs of 316 patients with heart failure (HF) were detected and quantitated by liquid chromatography-tandem mass spectrometry. Then, transverse aortic constriction (TAC)-induced HF was introduced in cardiomyocyte-specific Ephx2-/- mice. Moreover, Western blot, real-time PCR, luciferase reporter, ChIP assays were employed to explore the underlying mechanism. Finally, multiple sEH inhibitors were designed, synthesized, and validated in vitro and in vivo. RESULTS: The ratios of DHETs/EETs were increased in the plasma from patients with HF. Meanwhile, the expression of sEH was upregulated in the heart of patients and mice with HF, especially in cardiomyocytes. Cardiomyocyte-specific Ephx2-/- mice ameliorated cardiac dysfunction induced by TAC. Consistently, Ephx2 knockdown protected Angiotensin II (AngII)-treated cardiomyocytes via increasing EETs in vitro. Mechanistically, AngII could enhance the expression of transcript factor Krüppel-like factor 15 (KLF15), which in turn upregulated sEH. Importantly, glimepiride was identified as a novel sEH inhibitor, which benefited from the elevated EETs during HF. CONCLUSIONS: Glimepiride attenuates HF in mice in part by increasing EETs. CLINICAL TRIAL IDENTIFIER: NCT03461107 (https://clinicaltrials.gov).
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Epóxido Hidrolasas , Insuficiencia Cardíaca , Humanos , Ratones , Animales , Insuficiencia Cardíaca/tratamiento farmacológico , Eicosanoides/metabolismo , CorazónRESUMEN
Myocarditis is a challenging inflammatory disease of the heart, and better understanding of its pathogenesis is needed to develop specific drug therapies. Epoxyeicosatrienoic acids (EETs), active molecules synthesized by CYP (cytochrome P450) enzymes from arachidonic acids and hydrolyzed to less active dihydroxyeicosatrienoic acids by sEH (soluble epoxide hydrolase), have been attributed anti-inflammatory activity. Here, we investigated whether EETs have immunomodulatory activity and exert protective effects on coxsackie B3 virus-induced myocarditis. Viral infection altered eicosanoid epoxide and diol levels in both patients with myocarditis and in the murine heart and correlated with the increased expression and activity of sEH after coxsackie B3 virus infection. Administration of a sEH inhibitor prevented coxsackie B3 virus-induced cardiac dysfunction and inflammatory infiltration. Importantly, EET/sEH inhibitor treatment attenuated viral infection or improved viral resistance by activating type I IFN (interferon) signaling. At the molecular level, EETs enhanced the interaction between GSK3ß (glycogen synthase kinase-3 beta) and TBK1 (TANK-binding kinase 1) to promote IFN-ß production. Our findings revealed that EETs and sEH inhibitors prevent the progress of coxsackie B3 virus-induced myocarditis, particularly by promoting viral resistance by increasing IFN production.
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Glucocorticoids can induce chondrocyte autophagy. Lithium is a classical regulator of autophagy. The present study aimed to determine whether lithium can prevent glucocorticoidinduced chondrocyte autophagy by regulating the PI3K/AKT/mTOR signaling pathway. For this purpose, rat and human chondrocytes were treated with dexamethasone (200 µM) or dexamethasone (200 µM) combined with lithium chloride at various concentrations (0.01, 0.1, 1 and 10 mM). CYTOID® autophagy fluorescence staining and transmission electron microscopy were used to detect the levels of autophagy in the chondrocytes. Reverse transcriptionquantitative PCR and western blot analysis were used to measure the expression levels of the autophagy marker, LC3B and the autophagy regulatory signaling pathway (PI3K/AKT/mTOR signaling pathways) markers, AKT and mTOR. The viability of chondrocytes was measured using the Cell Counting Kit8 assay. It was found that compared with that in the control group, dexamethasone induced the autophagy of chondrocytes, decreased the expression levels of AKT and mTOR, and reduced cell viability. Compared with the treatment with dexamethasone alone, lithium chloride (10 mM) + dexamethasone reduced the autophagy levels, increased the expression level of AKT and mTOR, and increased cell viability. In conclusion, the present study demonstrated that lithium can prevent glucocorticoidinduced autophagy by activating the PI3K/AKT/mTOR signaling pathway and preventing the glucocorticoidinduced decrease in chondrocyte viability.