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BACKGROUD: Plasma lipids and alcohol intake frequency have been reported to be associated with the risk of osteoarthritis (OA). However, it remains inconclusive whether plasma lipids and alcohol intake frequency play a role in the development of OA. METHODS: The study employed a comprehensive genome-wide association database to identify independent genetic loci strongly linked to plasma lipids and alcohol intake frequency, which were used as instrumental variables. The causal association between plasma lipids, alcohol intake frequency, and the risk of OA was then analyzed using two-sample Mendelian randomization methods such as inverse variance weighted (IVW), MR-Egger regression, and weighted median estimator (WME), with odds ratios (ORs) as the evaluation criteria. RESULTS: A total of 392 SNPs were included as instrumental variables in this study, including 32 for total cholesterol (TC), 39 for triglycerides (TG), 170 for high-density lipoproteins (HDL), 60 for low-density lipoproteins (LDL), and 91 for alcohol intake frequency. Using the above two-sample Mendelian Randomization method to derive the causal association between exposure and outcome, with the IVW method as the primary analysis method and other MR analysis methods complementing IVW. The results of this study showed that four exposure factors were causally associated with the risk of OA. TC obtained a statistically significant result for IVW (OR = 1.207, 95% CI: 1.018-1.431, P = 0.031); TG obtained a statistically significant result for Simple mode (OR = 1.855, 95% CI: 1.107-3.109, P = 0.024); LDL obtained three statistically significant results for IVW, WME and Weighted mode (IVW: OR = 1.363, 95% CI: 1.043-1.781, P = 0.023; WME: OR = 1.583, 95% CI: 1.088-2.303, P = 0.016; Weighted mode: OR = 1.521, 95% CI: 1.062-2.178, P = 0.026). Three statistically significant results were obtained for alcohol intake frequency with IVW, WME and Weighted mode (IVW: OR = 1.326, 95% CI: 1.047-1.678, P = 0.019; WME: OR = 1.477, 95% CI: 1.059-2.061, P = 0.022; Weighted mode: OR = 1.641, 95% CI: 1.060-2.541, P = 0.029). TC, TG, LDL, and alcohol intake frequency were all considered as risk factors for OA. The Cochran Q test for the IVW and MR-Egger methods indicated intergenic heterogeneity in the SNPs contained in TG, HDL, LDL, and alcohol intake frequency, and the test for pleiotropy indicated a weak likelihood of pleiotropy in all causal analyses. CONCLUSIONS: The results of two-sample Mendelian randomization analysis showed that TC, TG, LDL, and alcohol intake frequency were risk factors for OA, and the risk of OA increased with their rise.
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Estudo de Associação Genômica Ampla , Osteoartrite , Humanos , Análise da Randomização Mendeliana , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Fatores de Risco , Osteoartrite/epidemiologia , Osteoartrite/genética , Triglicerídeos , Lipoproteínas HDLRESUMO
In situ growth of nanostructures on substrates is a strategy for designing highly efficient catalytic materials. Herein, multimetallic CuCoNi oxide nanowires are synthesized in situ on a three-dimensional nickel foam (NF) substrate (CuCoNi-NF) by a hydrothermal method and applied to peroxydisulfate (PDS) activation as immobilized catalysts. The catalytic performance of CuCoNi-NF is evaluated through the degradation of organic pollutants such as bisphenol A (BPA) and practical wastewater. The results indicate that the NF not only plays an important role as the substrate support but also serves as an internal Ni source for material fabrication. CuCoNi-NF exhibits high activity and stability during PDS activation as it mediates electron transfer from BPA to PDS. CuCoNi-NF first donates electrons to PDS to arrive at an oxidized state and subsequently deprives electrons from BPA to return to the initial state. CuCoNi-NF maintains high catalytic activity in the pH range of 5.2-9.2, adapts to a high ionic strength up to 100 mM, and resists background HCO3- and humic acid. Meanwhile, 76.6% of the total organic carbon can be removed from packaging wastewater by CuCoNi-NF-catalyzed PDS activation. This immobilized catalyst shows promising potential in wastewater treatment, well addressing the separation and recovery of conventional powdered catalysts.
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Nanofios , Óxidos , Catálise , Elétrons , Níquel , Oxirredução , Águas ResiduáriasRESUMO
Mantle cell lymphoma (MCL) is a lymphoproliferative disorder lacking reliable therapies. PI3K pathway contributes to the pathogenesis of MCL, serving as a potential target. However, idelalisib, an FDA-approved drug targeting PI3Kδ, has shown intrinsic resistance in MCL treatment. Here we report that a p300/CBP inhibitor, A-485, could overcome resistance to idelalisib in MCL cells in vitro and in vivo. A-485 was discovered in a combinational drug screening from an epigenetic compound library containing 45 small molecule modulators. We found that A-485, the highly selective catalytic inhibitor of p300 and CBP, was the most potent compound that enhanced the sensitivity of MCL cell line Z-138 to idelalisib. Combination of A-485 and idelalisib remarkably decreased the viability of three MCL cell lines tested. Co-treatment with A-485 and idelalisib in Maver-1 and Z-138 MCL cell xenograft mice for 3 weeks dramatically suppressed the tumor growth by reversing the unsustained inhibition in PI3K downstream signaling. We further demonstrated that p300/CBP inhibition decreased histone acetylation at RTKs gene promoters and reduced transcriptional upregulation of RTKs, thereby inhibiting the downstream persistent activation of MAPK/ERK signaling, which also contributed to the pathogenesis of MCL. Therefore, additional inhibition of p300/CBP blocked MAPK/ERK signaling, which rendered maintaining activation to PI3K-mTOR downstream signals p-S6 and p-4E-BP1, thus leading to suppression of cell growth and tumor progression and eliminating the intrinsic resistance to idelalisib ultimately. Our results provide a promising combination therapy for MCL and highlight the potential use of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumor.
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Classe Ia de Fosfatidilinositol 3-Quinase/efeitos dos fármacos , Linfoma de Célula do Manto/tratamento farmacológico , Purinas/uso terapêutico , Quinazolinonas/uso terapêutico , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Sinergismo Farmacológico , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Camundongos , Transplante de NeoplasiasRESUMO
Premature ejaculation is thought of as one of the most common male sexual dysfunctions, which is pathogenically very complex, involving the nervous, endocrine and muscular functions and psychology. With deeper insights into its pathophysiological mechanism, new therapies have been incessantly developed. At present, the first-line treatment of premature ejaculation is based on oral medication, but related drug resistance and adverse effects are evident. This review focuses on the neuromodulation therapies for premature ejaculation, including dorsal nerve block, local anesthetics, hyaluronic acid injections, and botulinum toxin, aiming to provide some reference for the treatment of different cases of premature ejaculation.
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In this study, a series of compounds with 1,2,4-oxadiazole core was designed and synthesized for the optimization of JC01, an anti-inflammatory hit identified from our in-house compound library using NF-κB pathway luciferase assay and NO production assay. All the synthetic compounds 1-29 have been screened for their anti-inflammatory effects by evaluating their inhibition against LPS-induced NO release, and compound 17 exhibited the highest activity. Western blotting and immunofluorescence analysis revealed that 17 prominently inhibited LPS-induced activation of NF-κB in RAW264.7 cells and blocked the phosphorylation of p65. Consistent with these results, it was found that 17 prevented the nuclear translocation of NF-κB induced by LPS. These data highlighted 17 as a promising anti-inflammatory agent by inhibiting NF-κB activity.
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Anti-Inflamatórios/farmacologia , Oxidiazóis/química , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/síntese química , Sobrevivência Celular , Desenho de Fármacos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A series of new coumarin/1,2,4-oxadiazole hybrids were synthesized and evaluated for cholinesterase inhibitory and neuroprotective activities. Among them, enantiomers 5u and 5v showed potent hBChE inhibitory activity with IC50 values of 8.17 and 9.56 µM, respectively, and also exhibited good selectivity for hBChE over hAChE by 9.49- and 7.58-fold, respectively. In addition, both compounds could protect SH-SY5Y cells against Aß25-35-induced neurotoxicity. The preliminary bioassay results provided a new chemotype for multifunctional anti-Alzheimer's disease agents and continuing investigation into compounds 5u and 5v is warranted.
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Doença de Alzheimer , Fármacos Neuroprotetores , Acetilcolinesterase , Inibidores da Colinesterase , Colinesterases , Cumarínicos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis , Relação Estrutura-AtividadeRESUMO
A series of new 1,2,3-triazole derivatives were synthesized and evaluated for anticholinesterase and neuroprotective activities. Some synthetic derivatives, especially compound 32, exhibited improved acetylcholinesterase (AChE) inhibitory activity by comparison with the hit 1, high selectivity toward AChE over butyrylcholinesterase (BuChE), and suitable in vitro neuroprotective effect against amyloid-ß25-35 (Aß25-35)-induced neurotoxicity in SH-SY5Y cells. Furthermore, these molecules have desired physicochemical properties in the range of CNS drugs and showed no cytotoxicity against two normal cells, including human keratinocytes HaCaT and murine fibroblasts NIH-3T3. The preliminary bioassay results and docking study indicated that compound 32 might be a promising lead compound with dual action for the treatment of Alzheimer's disease.
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Inibidores da Colinesterase/síntese química , Fármacos Neuroprotetores/síntese química , Triazóis/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Humanos , Ligação de Hidrogênio , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Triazóis/síntese químicaRESUMO
BACKGROUND: Osteoporosis (OP), characterized by low bone mass and increased fracture risk, is a prevalent skeletal disorder. Teriparatide (TP) and abaloparatide (ABL) are anabolic agents that may reduce fracture incidence, but their impact on musculoskeletal and connective tissue disorders (MCTD) risk is uncertain. RESEARCH DESIGN AND METHODS: A retrospective, observational disproportionality analysis was conducted utilizing FAERS data from Q1 2004 to Q3 2023, where TP or ABL was identified as the primary suspect drug. Multiple data mining algorithms, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to detect MCTD safety signals. RESULTS: A total of 366,747 TP-related and 422,377 ABL-related cases were identified, predominantly among female patients aged ≥45 years. The top specific AEs involved musculoskeletal, connective tissue, and administration site disorders. Comparative analysis revealed a higher frequency of AEs related to the nervous, cardiovascular, and gastrointestinal systems for ABL compared to TP. Both drugs exhibited strong signals for arthralgia, limb pain, back pain, muscle spasms, bone pain, muscle pain, and muscle weakness. CONCLUSION: The analysis suggests a potential MCTD risk with TP and ABL treatment in OP patients, highlighting the need for AE monitoring and management in clinical practice. This contributes to a better understanding of the safety profiles of these anabolic medications.
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Background: Teriparatide is approved for osteoporosis. Post-marketing surveillance is critical given its widespread use. Objective: To investigate adverse events (AEs) associated with teriparatide using the FAERS database, compare association strengths for key AEs, and explore potential applications to provide clinical reference. Methods: FAERS data from 2004 to 2023 were analyzed. Reports where teriparatide was the primary suspect drug were included. Adverse events were mapped to System Organ Classes and Preferred Terms. Disproportionality analysis using ROR, PRR, BCPNN and EBGM algorithms was conducted to detect safety signals. Results: Out of 107,123 reports with teriparatide as the primary suspect, key AEs identified included pain in extremity (PRR: 4.54), muscle spasms (PRR: 5.11), fractures (PRR range: 17.67-552.95), and increased calcium levels (PRR: 50.73). Teriparatide exhibited a stronger association with increased calcium levels (PRR: 50.73) compared to fractures (PRR range: 17.67-552.95). Notably, only 10.86% of AE reports were submitted by physicians and another 10% by other health professionals. Subset analyses showed a higher consistency of reported AEs from health professionals compared to the general dataset. Off-label uses were noted in conditions such as arthritis (0.57%) and cancer (0.12%). For osteoporosis, main AEs were pain (18.2%), fractures (12.4%), muscle spasms (7.7%), and nausea (6.5%), while glucocorticoid-induced osteoporosis AEs included fractures (24.1%), pain (13.2%), decreased bone density (9.8%), and nausea (5.1%). Conclusion: Our findings provide real-world safety data on teriparatide, revealing key AEs and their association strengths. The low proportion of reports by healthcare professionals suggests the need for cautious interpretation. Continuous vigilance and further research are imperative to guide teriparatide's clinical use.
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BACKGROUND: Non-Hodgkin's lymphoma (NHL) is a malignant tumor that originates from the lymphoid tissues and can potentially affect numerous organs within the body. Among these, the skin stands out as one of the primary sites affected by NHL, often presenting with multiple extra-nodal manifestations. In this report, we present an unusual case of NHL involving chronic wounds in the lower extremities that were difficult to heal. The scars were successfully treated using radiotherapy in combination with extended excision debridement and peroneal artery perforator flap grafting, resulting in satisfactory outcomes. CASE SUMMARY: A 19-year-old male patient presented with ulceration of the skin on the left calf near the ankle accompanied by purulent discharge. Subsequent pathologic biopsy confirmed a diagnosis of NHL (extranodal NK/T-cell lymphoma, nasal type). Initial treatment comprised local radiotherapy and wound care; however, the wound exhibited prolonged non-healing. Consequently, the patient underwent a series of interventions including radiotherapy, wound enlargement excision debridement, and peroneal artery perforator flap grafting. Ultimately, successful healing was achieved with favorable postoperative outcomes characterized by good texture of the flap without any signs of rupture or infection. CONCLUSION: The combination of radiotherapy, wound enlargement excision debridement, and peroneal artery perforator flap grafting may present a favorable treatment modality for chronic non-healing lower leg wounds resulting from NHL.
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Serving as neuromorphic hardware accelerators, memristors play a crucial role in large-scale neuromorphic computing. Herein, two-terminal memristors utilizing amorphous indium-gallium-zinc oxide (a-IGZO) are fabricated through room-temperature sputtering. The electrical characteristics of these memristors are effectively modulated by varying the oxygen flow during the deposition process. The optimized a-IGZO memristor, fabricated under 3 sccm oxygen flow, presents a 5 × 103 ratio between its high- and low-resistance states, which can be maintained over 1 × 104 s with minimal degradation. Meanwhile, desirable properties such as electroforming-free and self-compliance, crucial for low-energy consumption, are also obtained in the a-IGZO memristor. Moreover, analog conductance switching is observed, demonstrating an interface-type behavior, as evidenced by its device-size-dependent performance. The coexistence of negative differential resistance with analog switching is attributed to the migration of oxygen vacancies and the trapping/detrapping of charges. Furthermore, the device demonstrates optical storage capabilities by exploiting the optical properties of a-IGZO, which can stably operate for up to 50 sweep cycles. Various synaptic functions have been demonstrated, including paired-pulse facilitation and spike-timing-dependent plasticity. These functionalities contribute to a simulated recognition accuracy of 90% for handwritten digits. Importantly, a one-selector one-memristor (1S1M) architecture is successfully constructed at room temperature by integrating a-IGZO memristor on a TaOx-based selector. This architecture exhibits a 107 on/off ratio, demonstrating its potential to suppress sneak currents among adjacent units in a memristor crossbar.
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Cancer stem cells (CSCs) are crucial in the pathogenesis of human cancers. Existing studies reported that microRNA (miRNA) modulates the stemness of CSCs. We discovered that renal cell CSCs have suppressed miR-381. Suppression of miR-381 promotes renal cell tumorigenesis and CSC-like properties. Furthermore, the forced expression of miR-381 prevents the renal cell tumorigenesis and CSC-like properties. Mechanistically, renal cell CSCs have been found to interact with SOX4 through miR-381 directly. miR-381 inhibits renal cell CSC-like properties and tumorigenesis via downregulating SOX4. Examination of the patient-derived xenografts (PDX) and patient cohorts reveals that miR-381 may be able to forecast the advantages of Sunitinib in RCC patients. Moreover, the introduction of SOX4 could reverse the sensitivity of miR-381 overexpression RCC cells to Sunitinib-induced cell apoptosis. These results indicated that miR-381 is critical in renal cell CSC-like properties and tumorigenesis, making it the ideal therapeutic target for RCC.
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OBJECTIVE: The alteration in the mechanical environment of the necrotic area is the primary cause of the collapse observed in osteonecrosis of the femoral head (ONFH). This study aims to evaluate the biomechanical implications of the China-Japan Friendship Hospital (CJFH) classification system and hip flexion angles on the necrotic area in ONFH using finite element analysis (FEA). The goal is to provide valuable guidance for hip preservation treatments and serve as a reference for clinical diagnosis and therapeutic interventions. METHODS: Hip tomography CT scan data from a healthy volunteer was used to create a 3D model of the left hip. The model was preprocessed and imported into Solidworks 2018, based on the CJFH classification. Material parameters and boundary conditions were applied to each fractal model in ANSYS 21.0. Von Mises stresses were calculated, and maximum deformation values were obtained to evaluate the biomechanical effects of the load on the necrotic area and post-necrotic femur, as well as assess each fractal model's collapse risk. RESULTS: (1) At the same hip flexion angle, maximum deformation followed this order: M Type < C Type < L Type. The L3 type necrotic area experienced the most significant deformation at 0, 60, and 110° angles (1.121, 1.7913, and 1.8239 mm respectively). (2) Under the same CJFH classification, maximum deformation values increased with hip flexion angle (0 < 60 < 110°), suggesting a higher risk of collapse at larger angles. (3) Von Mises stress results showed that the maximum stress was not located in the necrotic area but near the inner and outer edge of the femoral neck, indicating decreased stiffness and strength of the subchondral bone after osteonecrosis. CONCLUSION: The study found that femoral head collapse risk was higher when the necrotic area was located in the lateral column under the same stress load and flexion angle. Mechanical properties of the necrotic area changed, resulting in decreased bone strength and stiffness. Large-angle hip flexion is more likely to cause excessive deformation of the necrotic area; thus, ONFH patients should reduce or avoid large-angle hip flexion during weight-bearing training in rehabilitation activities.
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Necrose da Cabeça do Fêmur , Cabeça do Fêmur , Humanos , Necrose da Cabeça do Fêmur/diagnóstico por imagem , Análise de Elementos Finitos , Amigos , Japão , ChinaRESUMO
Partial hepatectomy (PH) can lead to severe complications, including liver failure, due to the low regenerative capacity of the remaining liver, especially after extensive hepatectomy. Liver sinusoidal endothelial cells (LSECs), whose proliferation occurs more slowly and later than hepatocytes after PH, compose the lining of the hepatic sinusoids, which are the smallest blood vessels in the liver. Vascular endothelial growth factor (VEGF), secreted by hepatocytes, promotes LSEC proliferation. Supplementation of exogenous VEGF after hepatectomy also increases the number of LSECs in the remaining liver, thus promoting the reestablishment of the hepatic sinusoids and accelerating liver regeneration. At present, some shortcomings exist in the methods of supplementing exogenous VEGF, such as a low drug concentration in the liver and the reaching of other organs. More-over, VEGF should be administered multiple times and in large doses because of its short half-life. This review summarized the most recent findings on liver regeneration and new strategies for the localized delivery VEGF in the liver.
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Hepatectomia , Regeneração Hepática , Fator A de Crescimento do Endotélio Vascular , Humanos , Células Endoteliais/metabolismo , Hepatectomia/efeitos adversos , Hepatócitos/metabolismo , Fígado/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
A new electrophilic trifluoromethylselenolation reagent, N-trifluoromethylselenophthalimide (Phth-SeCF3), was developed. A strategy for the synthesis of 4-trifluoromethylselenolated isoxazoles through electrophilic trifluoromethylselenolation cyclization has been established by using Phth-SeCF3 as an electrophilic reagent. Moreover, this protocol has the features of broad substrate scope, good functional group tolerance, and high yields.
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BACKGROUND: The development of venous thromboembolism (VTE) is associated with high mortality among gastric cancer (GC) patients. Neutrophil extracellular traps (NETs) have been reported to correlate with the prothrombotic state in some diseases, but are rarely reported in GC patients. AIM: To investigate the effect of NETs on the development of cancer-associated thrombosis in GC patients. METHODS: The levels of NETs in blood and tissue samples of patients were analyzed by ELISA, flow cytometry, and immunofluorescence staining. NET generation and hypercoagulation of platelets and endothelial cells (ECs) in vitro were observed by immunofluorescence staining. NET procoagulant activity (PCA) was determined by fibrin formation and thrombin-antithrombin complex (TAT) assays. Thrombosis in vivo was measured in a murine model induced by flow stenosis in the inferior vena cava (IVC). RESULTS: NETs were likely to form in blood and tissue samples of GC patients compared with healthy individuals. In vitro studies showed that GC cells and their conditioned medium, but not gastric mucosal epithelial cells, stimulated NET release from neutrophils. In addition, NETs induced a hypercoagulable state of platelets by upregulating the expression of phosphatidylserine and P-selectin on the cells. Furthermore, NETs stimulated the adhesion of normal platelets on glass surfaces. Similarly, NETs triggered the conversion of ECs to hypercoagulable phenotypes by downregulating the expression of their intercellular tight junctions but upregulating that of tissue factor. Treatment of normal platelets or ECs with NETs augmented the level of plasma fibrin formation and the TAT complex. In the models of IVC stenosis, tumor-bearing mice showed a stronger ability to form thrombi, and NETs abundantly accumulated in the thrombi of tumor-bearing mice compared with control mice. Notably, the combination of deoxyribonuclease I, activated protein C, and sivelestat markedly abolished the PCA of NETs. CONCLUSION: GC-induced NETs strongly increased the risk of VTE development both in vitro and in vivo. NETs are potential therapeutic targets in the prevention and treatment of VTE in GC patients.
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Armadilhas Extracelulares , Neoplasias Gástricas , Trombofilia , Trombose , Tromboembolia Venosa , Animais , Constrição Patológica , Células Endoteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Fibrina , Camundongos , Neutrófilos/metabolismo , Neoplasias Gástricas/complicações , Neoplasias Gástricas/metabolismo , Trombose/etiologia , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/metabolismoRESUMO
PURPOSE: Steroid-induced osteonecrosis of the femoral head (SONFH) is a refractory orthopaedic hip joint disease that occurs in young- and middle-aged people. Previous experimental studies have shown that autophagy might be involved in the pathological process of SONFH, but the pathogenesis of autophagy in SONFH remains unclear. We aimed to identify and validate the key potential autophagy-related genes involved in SONFH to further illustrate the mechanism of autophagy in SONFH through bioinformatics analysis. METHODS: The GSE123568 mRNA expression profile dataset, including 10 non-SONFH (following steroid administration) samples and 30 SONFH samples, was downloaded from the Gene Expression Omnibus (GEO) database. Autophagy-related genes were obtained from the Human Autophagy Database (HADb). The autophagy-related genes involved in SONFH were screened by intersecting the GSE123568 dataset with the set of autophagy genes. The differentially expressed autophagy-related genes involved in SONFH were identified with R software. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the differentially expressed autophagy-related genes involved in SONFH were conducted by using R software. Then, the correlations between the expression levels of the differentially expressed autophagy-related genes involved in SONFH were confirmed with R software. Moreover, the protein-protein interaction (PPI) network was analysed by using the Search Tool for the Retrieval of Interacting Genes (STRING), significant gene cluster modules were identified with the MCODE Cytoscape plugin, and hub genes among the differentially expressed autophagy-related genes involved in SONFH were screened by using the CytoHubba Cytoscape plugin. Finally, the expression levels of the hub genes of the differentially expressed autophagy-related genes involved in SONFH were validated in hip articular cartilage specimens from necrotic femur heads (NFHs) by using the GSE74089 dataset and further verification by qRT-PCR. RESULTS: A total of 34 differentially expressed autophagy-related genes were identified between the peripheral blood samples of SONFH patients and non-SONFH patients based on the defined criteria, including 25 upregulated genes and 9 downregulated genes. The GO and KEGG pathway enrichment analyses revealed that these 34 differentially expressed autophagy-related genes involved in SONFH were particularly enriched in death domain receptors, the FOXO signalling pathway and apoptosis. Correlation analysis revealed significant correlations among the 34 differentially expressed autophagy-related genes involved in SONFH. The PPI results demonstrated that the 34 differentially expressed autophagy-related genes interacted with each other. Ten hub genes were identified by using the MCC algorithms of CytoHubba. The GSE74089 dataset showed that TNFSF10, PTEN and CFLAR were significantly upregulated while BCL2L1 was significantly downregulated in the hip cartilage specimens, which was consistent with the GSE123568 dataset. TNFSF10, PTEN and BCL2L1 were detected with consistent expression by qRT-PCR. CONCLUSIONS: Thirty-four potential autophagy-related genes involved in SONFH were identified via bioinformatics analysis. TNFSF10, PTEN and BCL2L1 might serve as potential drug targets and biomarkers because they regulate autophagy. These results expand the autophagy-related understanding of SONFH and might be useful in the diagnosis and prognosis of SONFH.
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Autofagia/genética , Biologia Computacional/métodos , Necrose da Cabeça do Fêmur/induzido quimicamente , Esteroides/efeitos adversos , Feminino , Necrose da Cabeça do Fêmur/genética , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , OsteonecroseRESUMO
Liver fibrosis occurs following inflammation triggered by the integrated actions of activated liver-resident macrophages (Kupffer cells) and hepatic stellate cells (HSCs), and the multiplicity of these mechanisms complicates drug therapy. Here, we demonstrate that the selective bromodomain and extra-terminal (BET) bromodomain inhibitor compound38 can block both the Janus kinase-signal transducer and activator of transcription and mitogen-activated protein kinase signaling pathways in macrophages, which decreased their secretion of proinflammatory cytokines in a dose-dependent manner. The inactivation of macrophages attenuated lipopolysaccharide-induced injurious inflammation concurrent with a reduction in F4/80+ cells, proinflammatory cytokine levels, and neutrophil infiltration. Moreover, compound 38 inhibited the Wnt/ß-catenin and transforming growth factor-beta/SMAD signaling pathways to abolish the activation of HSCs. In vivo, compound 38 significantly decreased the collagen deposition and fibrotic area of a CCl4-induced liver fibrosis model, and restored the deficiency of activated HSCs and the upregulation of liver inflammation. These results highlight the potential role of compound 38 in treating liver fibrosis considering its simultaneous inhibitory effects on liver inflammation and related fibrosis.
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Células Estreladas do Fígado , Cirrose Hepática , Citocinas/metabolismo , Células Estreladas do Fígado/metabolismo , Humanos , Inflamação/metabolismo , Cirrose Hepática/tratamento farmacológico , Macrófagos/metabolismoRESUMO
In order to understand the characteristics of soil nitrogen and phosphorus loss under different land use patterns in the small watershed of the Three Gorges Reservoir area and provide a scientific basis for the prevention and control of agricultural non-point source pollution, a field test method was used to study the paddy fields and drought in the small Shipanqiu Watershed in the Three Gorges Reservoir area. The characteristics of different runoff concentrations and the fluxes of nitrogen and phosphorus in surface runoff under the five land use schemes of paddy filed, slope land, woodlands, citrus orchards, and vegetable land. The results show that the annual total nitrogen loss followed the order of paddy field[17.73 kg·(hm2·a)-1] > citrus orchards[4.86 kg·(hm2·a)-1] > dry slope land[4.33 kg·(hm2·a)-1] > vegetable field[4.00 kg·(hm2·a)-1] > woodland[2.41 kg·(hm2·a)-1]. The annual total phosphorous loss followed the order of vegetable fields[4.97 kg·(hm2·a)-1] > Citrus orchards[1.87 kg·(hm2·a)-1] > paddy fields[0.93 kg·(hm2·a)-1] > woodlands[0.27 kg·(hm2·a)-1] > dry slope land[0.19 kg·(hm2·a)-1]. The nitrogen and phosphorus losses under the five land use methods were mainly concentrated from April to May with frequent rainfall events, accounting for 53.80%-96.52% and 56.03%-87.78% of the total annual nitrogen and phosphorus losses. Nitrogen loss was mainly in the form of nitrate nitrogen (16.16%-52.70%), and the total nitrogen loss flux and runoff showed a significant positive correlation (R2=0.9826). Particulate phosphorus was the main form of phosphorus loss in vegetable fields (83.30%), but in other land use schemes it is not significant. There were significant differences in the loss of different forms of nitrogen and phosphorus under the different land use schemes. Among them, measures should be taken in vegetable fields to deal with the problem of particulate phosphorus loss under conditions of heavy rainfall. Fertilization should be avoided in paddy fields during periods of concentrated rainfall. Scientific fertilization and reasonable land use configurations are important ways to control agricultural non-point source pollution in small watersheds.
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BACKGROUND: Paratesticular liposarcoma accounts for approximately 7% of scrotal tumors. They are rare lesions of the reproductive system with approximately 90% of the lesions originating from the spermatic cord. Surgery, with the goal of complete resection, is the mainstay for treatment of this disease. However, treatment consisting of extended resection to decrease local recurrence remains controversial. CASE SUMMARY: We report the cases of two patients with paratesticular liposarcomas who were treated with radical testicular tumor resection without adjuvant therapy. Follow-up investigations at 9 mo showed no sign of recurrence. CONCLUSION: Surgery is the first-line treatment, regardless of whether it is a recurrent or primary tumor. Extended resection carries a higher risk of complications and should not be performed routinely. Preoperative radiotherapy can reduce the local recurrence rate without affecting the overall survival.