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1.
J Pharm Pharmacol ; 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36718013

RESUMO

OBJECTIVE: Honokiol, a natural active compound extracted from Chinese herbal medicine, can ameliorate acute lung and kidney injury of sepsis. This study was to explore the effects of honokiol on sepsis-associated cardiac dysfunction and the underlying mechanism. METHODS: Septic mice were induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS), and septic HL-1 or AC16 cells were induced by LPS. RESULTS: Honokiol improved the survival and alleviated cardiac dysfunction in mice with CLP-induced sepsis. Honokiol inhibited the increased interleukin (IL) 1-ß, IL-6 and tumour necrosis factor (TNF)-α in the serum and heart of CLP- and LSP-induced septic mice. Honokiol treatment reversed the increased levels of IL1-ß, IL-6 and TNF-α in LPS-induced HL-1 cells. Honokiol treatment also decreased the elevated levels of IL1-ß, IL-6 and TNF-α in LPS-induced AC16 cells. The increased cardiac apoptosis in CLP- and LPS-induced septic mice was alleviated by honokiol. The enhancement of oxidative stress in the heart of CLP- and LPS-induced septic mice was suppressed after honokiol administration. CONCLUSION: These results showed that honokiol could ameliorate sepsis-associated cardiac dysfunction via attenuating inflammation, apoptosis, and oxidative stress. Honokiol is a prospective drug for sepsis-associated heart damage in the future.

2.
PLoS One ; 18(1): e0279530, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36630382

RESUMO

The interest in edible insects as food is growing, both in traditional and non-traditional insect-eating countries given their advantages in terms of sustainability and nutritional content. However, only a few studies have conducted cross-country investigations on the acceptance of including processed or whole insects in the diet. Thus, this study aimed to examine to which extent consumers were accepting (i) whole and visible mealworms, (ii) processed mealworms in their diet and (iii) to explore the factors affecting the acceptance level of consuming mealworms in countries with and without entomophagy tradition. An online survey was applied to collect responses (3,006) from five countries-i.e., Belgium, China, Italy, Mexico, and the US-using a quota sampling method. Moreover, an information treatment was included with about half of the participants receiving information about the advantages of edible insects as food (ingredient) and the presence of food safety regulations. Across countries, gender was the main factor affecting acceptance level as men accepted mealworms more than women. Entomophagy tradition mainly explained the differences among countries. Countries with entomophagy traditions (Mexico and China) showed higher acceptance of including whole or processed mealworms in the diet compared to countries with no entomophagy traditions (i.e., Belgium, Italy, and the US). While information and age did affect differently the acceptance of including processed mealworms in countries with entomophagy traditions showing that consumer acceptance was affected by information in Mexico and by age in China. Whereas it was found that younger people (below 42 years old) in countries without entomophagy tradition were more open to accepting processed mealworms in their diet. Moreover, across countries, the acceptance of including processed mealworms was higher compared to whole mealworms. These findings provide insights into which consumer segments to target and the potential impact of information when introducing new insect-based foods in countries with and without entomophagy traditions.


Assuntos
Insetos Comestíveis , Tenebrio , Masculino , Animais , Humanos , Feminino , Adulto , Bélgica , México , Insetos , Itália , China
3.
Anat Rec (Hoboken) ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36691370

RESUMO

Bone marrow mesenchymal stem cells (BMSCs) have the ability to differentiate into chondrocytes. In the differentiation of BMSCs into chondrocytes, micro-RNAs (miRNAs) play an important role. rno-miR-90 is a new miRNA discovered by our research team, and its role in chondrogenic differentiation of BMSCs is unknown. This study aimed to investigate whether rno-miR-90 could promote chondrogenic differentiation of BMSCs by regulating secreted protein acidic and rich in cysteine-related modular calcium binding 2 (Smoc2). First, BMSCs chondroblast differentiation was successfully induced in vitro by classical induction method of transforming growth factor (TGF)-ß3. On this basis, we transfected rno-miR-90 mimic and inhibitor, and confirmed that rno-miR-90 mimic could promote the differentiation of BMSCs into chondrocytes by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. In addition, we demonstrated that Smoc2 was a target gene of rno-miR-90 by dual-luciferase reporter assay, and confirmed that rno-miR-90 mimic could inhibit the expression of Smoc2 by RT-qPCR and western blotting. In order to further prove the targeting relationship between rno-miR-90 and Smoc2, we constructed three interfering fragments of Smoc2, and proved that silencing Smoc2 could promote the differentiation of BMSCs into chondrocytes at the transcriptional and protein levels. Finally, we constructed a carrier scaffold for ectopic chondrogenic differentiation in vivo, and confirmed that rno-miR-90 mimic and siSmoc2 could promote chondrogenic differentiation of BMSCs by Alcian blue staining and immunohistochemistry. In summary, our results suggested that rno-miR-90 could promote chondrogenic differentiation of BMSCs by down-regulating the expression of Smoc2. rno-miR-90 mimic and Smoc2 may be therapeutic targets of osteoarthritis.

4.
Adv Ther ; 2022 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-36463561

RESUMO

BACKGROUND: Although the bortezomib-based triple-drug therapy is considered as a front-line therapy for multiple myeloma (MM) in Chinese patients, increased level of toxicity leads to treatment dissatisfaction. Treatment with ixazomib, an oral proteasome inhibitor, has demonstrated better efficacy and safety profile without increasing the toxicity. In this study, we investigate the safety and clinical outcomes of Chinese patients with newly diagnosed MM (NDMM) who transitioned from a bortezomib-based triple-drug therapy to an ixazomib-based triple-drug therapy in a real-world clinical setting. METHODS: This will be an open-label, single-arm, multicenter, prospective, observational study will recruit Chinese patients (aged ≥ 18 years) diagnosed with NDMM using International Myeloma Working Group (IMWG) criteria and who have received a bortezomib-based triple-drug therapy for more than two cycles as initial therapy. The previous bortezomib-based triple-drug therapy may include bortezomib, cyclophosphamide, and dexamethasone or lenalidomide, bortezomib, and dexamethasone or bortezomib, doxorubicin, and dexamethasone or bortezomib, thalidomide, and dexamethasone. At the time of enrollment, patients must have achieved at least partial response as defined by IMWG criteria. Approximately 320 eligible patients at 15 top MM hospitals in China will be treated with ixazomib triple-drug therapy and followed up once every 3 months for 24 months, unless specified. The primary endpoint is to assess progression-free survival at 2 years for Chinese patients with NDMM who have transitioned from a bortezomib-based triple-drug therapy to ixazomib-based triple-drug therapy. The clinical effectiveness, safety and tolerability, patient-reported outcomes, and health economic/resource utilization will be evaluated as secondary endpoints. PLANNED OUTCOMES: The results from this study may provide evidence to verify the benefits of transitioning from bortezomib-based triple-drug therapy to ixazomib-based triple-drug therapy in Chinese patients with NDMM in a real-world clinical setting. TRIAL REGISTRATION: The study has been registered at clinicalTrials.gov (NCT05013190).

5.
BMC Mol Cell Biol ; 23(1): 58, 2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36526996

RESUMO

BACKGROUND: Cold inducible RNA-binding protein (CIRP) is a key protein in the hypothermic therapy. Highly expressed CIRP exerts a neuroprotective effect on neurons. The aim of this study is to provide the evidence of the protective effects of CIRP on the glial cells and explore the downstream pathway of CIRP. RESULTS: The results of this study demonstrated that the cell viability of the glial cells with CIRP overexpression was increased significantly compared to the control. With CIRP overexpression, the epidermal growth factor (EGF) mRNA expression was found increasing significantly and the mRNA expressions of derived neurotrophic factor (BDNF), bcl-2, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) were not upregulated compared to the control. EGF and CIRP co-expression was demonstrated on the glial cells. With CIRP expression, EGF expression on the glial cells was increased statistically compared to the control. CONCLUSION: CIRP overexpression increases the cell viability of the glial cells, exerting a neuroprotective effect. EGF expression is activated on the glial cells with CIRP overexpression, implying a pathway of CIRP neuroprotection via EGF activation.


Assuntos
Fator de Crescimento Epidérmico , Fármacos Neuroprotetores , Sobrevivência Celular , Fator de Crescimento Epidérmico/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fator A de Crescimento do Endotélio Vascular , Neuroglia/metabolismo , RNA Mensageiro/genética
6.
Foods ; 11(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36360107

RESUMO

This study aimed to identify factors that influence the decisions of rooibos farmers in South Africa to implement certification and quality assurance systems. The study was conducted in the Western Cape region of South Africa. A structured questionnaire was distributed to 300 farmers in the form of interviews. In addition, an analysis of previously published data was also used. Results showed that membership in an association, land tenure, rooibos tea farm size, and education level were the main determinants of implementing certifications and quality assurance systems. Membership in the association and land tenure significantly negatively affected the adoption of certification. In contrast, farm size and level of education, translating to knowledge of certification systems, tended to have a significant positive effect on adoption. Continuous education, awareness of the process of certification and quality assurance systems, and the formation of farmers' support systems are recommended to improve the impact of smallholder rooibos farmers in the industry.

7.
Cancer Med ; 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36271592

RESUMO

BACKGROUND: The use of proteasome inhibitors (PIs), new immune modulators (IMiDs), and other new drugs, as well as high-dose chemotherapy combined with autologous stem cell transplantation has considerably improved the survival of young patients with multiple myeloma (MM). However, the improvement in survival among elderly patients remains insufficient. Optimal treatment recommendation models for elderly patients with MM have not been developed especially there are quite few study in the real world. METHODS: We retrospectively analyzed the treatment patterns and outcomes of 328 Chinese patients (≥65 years) with MM in a real-world setting. Patients were divided into three groups according to induction regimens. RESULTS: The median age of the cohort was 70 (65-86) years. The patients were divided into group 1 (PIs based regimens, n = 218), group 2 (IMiDs based regimens, n = 48) and group 3 (PIs + IMiDs, n = 62). Induction regimens in group 3 produced higher overall response rate than group 1 and 2 (85.42% vs. 71.08% vs. 66.67%, p = 0.016). The median follow-up of the cohort was 30 (interquartile range [IQR] 18-36) months. For the entire cohort median progression-free survival (PFS) was 26 (IQR 12.00-42.89) months and overall survival (OS) was 60 (IQR 40.00-67.20) months. The PFS were not significantly different among the three groups (28 months vs. 18 months vs. 26 months, p = 0.182). So were the OS (60 months vs. 59 months vs. not reached, p = 0.067). Multivariate analysis revealed that age >70 year, frailty status (Geriatric vulnerability score), induction efficacy < partial remission, and no maintenance treatment were independent poor prognostic factors for OS. CONCLUSION: Front-line induction regimens combining PIs and IMiDs developed more deep response than single PI or IMiD based regimens. Maintenance treatment can further improve the clinical outcome in elderly MM patients in real-world setting.

8.
Int J Stem Cells ; 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36310024

RESUMO

Background and Objectives: Osteoarthritis (OA) is a degenerative disease that leads to the progressive destruction of articular cartilage. Current clinical therapeutic strategies are moderately effective at relieving OA-associated pain but cannot induce chondrocyte differentiation or achieve cartilage regeneration. We investigated the ability of wedelolactone, a biologically active natural product that occurs in Eclipta alba (false daisy), to promote chondrogenic differentiation. Methods and Results: Real-time reverse transcription-polymerase chain reaction, immunohistochemical staining, and immunofluorescence staining assays were used to evaluate the effects of wedelolactone on the chondrogenic differentiation of mesenchymal stem cells (MSCs). RNA sequencing, microRNA (miRNA) sequencing, and isobaric tags for relative and absolute quantitation analyses were performed to explore the mechanism by which wedelolactone promotes the chondrogenic differentiation of MSCs. We found that wedelolactone facilitates the chondrogenic differentiation of human induced pluripotent stem cell-derived MSCs and rat bone-marrow MSCs. Moreover, the forkhead box O (FOXO) signaling pathway was upregulated by wedelolactone during chondrogenic differentiation, and a FOXO1 inhibitor attenuated the effect of wedelolactone on chondrocyte differentiation. We determined that wedelolactone reduces enhancer of zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation of the promoter region of FOXO1 to upregulate its transcription. Additionally, we found that wedelolactone represses miR-1271-5p expression, and that miR-1271-5p post-transcriptionally suppresses the expression of FOXO1 that is dependent on the binding of miR-1271-5p to the FOXO1 3'-untranscribed region. Conclusions: These results indicate that wedelolactone suppresses the activity of EZH2 to facilitate the chondrogenic differentiation of MSCs by activating the FOXO1 signaling pathway. Wedelolactone may therefore improve cartilage regeneration in diseases characterized by inflammatory tissue destruction, such as OA.

9.
Diagn Pathol ; 17(1): 76, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36199118

RESUMO

Skin metastasis of ovarian cancer is extremely rare. We report an unusual case of ovarian carcinosarcoma with cutaneous metastasis of carcinomatous component that displayed distinct clinical manifestation. A 48-year-old woman presented to the dermatologist complaining of a new onset of erythematous, plaque-like skin rash with multiple small nodules on the left inner thigh, the area measuring 8 × 5cm. While the patient had no history of dermatologic conditions, she underwent a total hysterectomy and bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection 16 months ago with a pathology confirmed stage IIIC ovarian carcinosarcoma. Of note, the carcinomatous component, mainly adenocarcinoma with hybrid features of seromucinous, endometrioid and minor high-grade serous carcinoma, involved bilateral fallopian tubes, omentum, and parametrium with extensive lymph node metastases. A skin biopsy specimen revealed an adenocarcinoma involving epidermis, dermis, and subcutaneous tissue with nodular contours, consistent with metastatic carcinomatous component of carcinosarcoma. Both carcinomatous component of primary ovarian carcinosarcoma and metastatic adenocarcinoma in the skin demonstrated Pax8, WT-1, and ER positivity and a mutation pattern of p53. The patient passed away 15 months after identification of skin metastasis. This case represents a unique example of cutaneous metastasis of ovarian carcinosarcoma with distinct clinical manifestation and detailed histopathological description. Alertness to the possibility of cutaneous metastasis, in combination with clinical history, morphological and immunohistochemical findings, is critical for a definitive classification.


Assuntos
Adenocarcinoma , Carcinossarcoma , Neoplasias Ovarianas , Neoplasias Cutâneas , Carcinossarcoma/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Cutâneas/patologia , Proteína Supressora de Tumor p53
10.
J Cancer ; 13(13): 3463-3475, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36313040

RESUMO

Over the past two decades, the global efforts for the early detection and intervention of prostate cancer seem to have made significant progresses in the basic researches, but the clinic outcomes have been disappointing: (1) prostate cancer is still the most common non-cutaneous cancer in Europe in men, (2) the age-standardized prostate cancer rate has increased in nearly all Asian and African countries, (3) the proportion of advanced cancers at the diagnosis has increased to 8.2% from 3.9% in the USA, (4) the worldwide use of PSA testing and digital rectal examination have failed to reduce the prostate cancer mortality, and (5) there is still no effective preventive method to significantly reduce the development, invasion, and metastasis of prostate cancer… Together, these facts strongly suggest that the global efforts during the past appear to be not in a correlated target with markedly inconsistent basic research and clinic outcomes. The most likely cause for the inconsistence appears due to the fact that basic scientific studies are traditionally conducted on the cell lines and animal models, where it is impossible to completely reflect or replicate the in vivo status. Thus, we would like to propose the human prostate basal cell layer (PBCL) as "the most effective target for the early detection and intervention of prostate cancer". Our proposal is based on the morphologic, immunohistochemical and molecular evidence from our recent studies of normal and cancerous human prostate tissues with detailed clinic follow-up data. We believe that the human tissue-derived basic research data may provide a more realistic roadmap to guide the clinic practice and to avoid the potential misleading from in vitro and animal studies.

11.
Nat Commun ; 13(1): 5968, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-36216793

RESUMO

Small cell cervical carcinoma (SCCC) is a rare but aggressive malignancy. Here, we report human papillomavirus features and genomic landscape in SCCC via high-throughput HPV captured sequencing, whole-genome sequencing, whole-transcriptome sequencing, and OncoScan microarrays. HPV18 infections and integrations are commonly detected. Besides MYC family genes (37.9%), we identify SOX (8.4%), NR4A (6.3%), ANKRD (7.4%), and CEA (3.2%) family genes as HPV-integrated hotspots. We construct the genomic local haplotype around HPV-integrated sites, and find tandem duplications and amplified HPV long control regions (LCR). We propose three prominent HPV integration patterns: duplicating oncogenes (MYCN, MYC, and NR4A2), forming fusions (FGFR3-TACC3 and ANKRD12-NDUFV2), and activating genes (MYC) via the cis-regulations of viral LCRs. Moreover, focal CNA amplification peaks harbor canonical cancer genes including the HPV-integrated hotspots within MYC family, SOX2, and others. Our findings may provide potential molecular criteria for the accurate diagnosis and efficacious therapies for this lethal disease.


Assuntos
Alphapapillomavirus , Carcinoma de Células Pequenas , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Proteínas Associadas aos Microtúbulos/genética , Proteína Proto-Oncogênica N-Myc/genética , Proteínas Nucleares/genética , Papillomaviridae/genética , Neoplasias do Colo do Útero/patologia , Integração Viral/genética
12.
Oxid Med Cell Longev ; 2022: 1652244, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36299604

RESUMO

Corilagin, a gallotannin, shows excellent antioxidant and anti-inflammatory effects. The NLRP3 inflammasome dysfunction has been implicated in a variety of inflammation diseases. However, it remains unclear how corilagin regulates the NLRP3 inflammasome to relieve gouty arthritis. In this study, bone marrow-derived macrophages (BMDMs) were pretreated with lipopolysaccharide (LPS) and then incubated with NLRP3 inflammasome agonists, such as adenine nucleoside triphosphate (ATP), nigericin, and monosodium urate (MSU) crystals. The MSU crystals were intra-articular injected to induce acute gouty arthritis. Here we showed that corilagin reduced lactate dehydrogenase (LDH) secretion and the proportion of propidium iodide- (PI-)stained cells. Corilagin suppressed the expression of N-terminal of the pyroptosis executive protein gasdermin D (GSDMD-NT). Corilagin restricted caspase-1 p20 and interleukin (IL)-1ß release. Meanwhile, corilagin attenuated ASC oligomerization and speck formation. Our findings confirmed that corilagin diminished NLRP3 inflammasome activation and macrophage pyroptosis. We further discovered that corilagin limited the mitochondrial reactive oxygen species (ROS) production and prevented the interaction between TXNIP and NLRP3, but ROS activator imiquimod could antagonize the inhibitory function of corilagin on NLRP3 inflammasome and macrophage pyroptosis. Additionally, corilagin ameliorated MSU crystals induced joint swelling, inhibited IL-1ß production, and abated macrophage and neutrophil migration into the joint capsule. Collectively, these results demonstrated that corilagin suppressed the ROS/TXNIP/NLRP3 pathway to repress inflammasome activation and pyroptosis and suggest its potential antioxidative role in alleviating NLRP3-dependent gouty arthritis.


Assuntos
Artrite Gotosa , Piroptose , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Taninos Hidrolisáveis/farmacologia , Taninos Hidrolisáveis/uso terapêutico , Lipopolissacarídeos/farmacologia , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/metabolismo , Ácido Úrico/uso terapêutico , Antioxidantes/farmacologia , Nigericina/farmacologia , Nigericina/uso terapêutico , Imiquimode/farmacologia , Imiquimode/uso terapêutico , Propídio/farmacologia , Propídio/uso terapêutico , Nucleosídeos/farmacologia , Caspase 1/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Anti-Inflamatórios/farmacologia , Trifosfato de Adenosina/farmacologia , Adenina/farmacologia , Lactato Desidrogenases
13.
Front Immunol ; 13: 962056, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36189233

RESUMO

Background: Tertiary lymphoid structures (TLSs) are crucial in promoting and maintaining positive anti-tumor immune responses. The tumor stroma has a powerful immunosuppressive function that could exclude tumor-infiltrating lymphocytes from the tumor beds and lead to a "cold" phenotype. TLSs and tumor stroma percentage (TSP) are significantly associated with the prognosis of patients with certain cancers. However, the exact roles of TLSs and TSP and their intrinsic relationship are still largely unknown in colorectal cancer (CRC). Methods: TLSs and TSP were assessed using hematoxylin-eosin (H&E) and/or immunohistochemistry (IHC) staining from 114 CRC patients in the training set and 60 CRC patients in the external validation set. The correlation between TILs, TLS and clinicopathological characteristics and their prognostic values were assessed. Finally, we plotted a Nomogram including the TLS, TSP and tumor-node-metastasis (TNM) stage to predict the probability of recurrence-free survival (RFS) at 2- and 5-years in non-metastatic colorectal cancer (nmCRC) patients. Results: Peritumoral TLS (P-TLS), intratumoral TLS (In-TLS) and high TSP (H-TSP, >50%) were present in 99.1%, 26.3% and 41.2% patients, respectively. H-TSP tumor tends to be associated with lower P-TLS density (P =0.0205). The low P-TLS density (< 0.098/mm2) was significantly associated with reduced RFS (HR=6.597 95% CI: 2.882-15.103, P <0.001) and reduced overall survival (OS) (HR=6.628 95% CI: 2.893-15.183, P < 0.001) of nmCRC patients. In-TLS was not of significance in evaluating the clinical outcomes of nmCRC patients. H-TSP was significantly associated with reduced RFS (HR=0.126 95% CI: 0.048-0.333, P <0.001) and reduced OS (HR=0.125 95% CI: 0.047-0.332, P <0.001) of nmCRC patients. The 5-year RFS of the high P-TLS, low-TLS, H-TSP, and L-TSP groups were 89.7%, 47.2%, 53.2%, and 92.5%, respectively. The P-TLS density, TSP and TNM stage were independent prognosis factors of nmCRC patients. The Nomogram, including the P-TLS density, TSP and TNM stage, outperformed the TNM stage. Conclusions: High P-TLS density and low TSP (L-TSP) were independent and favorable prognostic factors of nmCRC patients, which might provide new directions for targeted therapy in the CRC tumor microenvironment, especially the tumor immune microenvironment.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Estruturas Linfoides Terciárias , Neoplasias Colorretais/patologia , Amarelo de Eosina-(YS) , Hematoxilina , Humanos , Prognóstico , Microambiente Tumoral
14.
Phytomedicine ; 107: 154447, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36150345

RESUMO

BACKGROUND: Diabetic ulcers, which are characterized by chronic nonhealing wounds with a long-lasting inflammatory state, are a typical symptom in individuals with diabetes, and there is still no effective treatment for these lesions. Angelica dahurica plays a critical role in inflammatory diseases. Among numerous monomeric compounds, phellopterin has been shown to have anti-inflammatory properties. PURPOSE: To research the bioactive constituents in Angelica dahurica and their mechanism of action in treating diabetic ulcers. STUDY DESIGN: Chemical research of Angelica dahurica led to the identification of a new coumarin, dahuricoumarin A (1), along with seven known compounds (2 - 8). All compounds were tested for anti-inflammatory activity, and phellopterin, compound (3), significantly decreased the expression of intercellular cell adhesion molecule-1 (ICAM-1), a representative indicator of inflammation. Phellopterin can also increase SIRT1 protein, a key target for inflammation. In our research, we confirmed the anti-inflammatory effects of phellopterin on diabetic ulcers and explored the underlying mechanism of action. METHODS: The expression of IFN-γ, SIRT1, and ICAM-1 in human diabetic ulcer tissues was studied using immunohistochemistry. Streptozotocin was used to induce a diabetic model in C57BL/6J mice, and ulcers were surgically introduced. After phellopterin treatment, the skin lesions of diabetic mice were observed over a period of time. The protein and mRNA expression levels of SIRT1 and ICAM-1 were measured using H&E, qRT-PCR and immunohistochemical staining. A HaCaT cell inflammatory model was induced by IFN-γ. Using a lentiviral packaging technique, MTT assay, and Western blotting, the effect of phellopterin on the proliferation of HaCaT cells and the expression of ICAM-1 was evaluated under normal and SIRT1 knockdown conditions. RESULTS: High levels of ICAM-1 and IFN-γ were identified, but low levels of SIRT1 were found in human diabetic ulcer tissues, and phellopterin showed therapeutic benefits in the healing process by attenuating chronic inflammation and promoting re-epithelialization, along with SIRT1 upregulation and ICAM-1 downregulation. However, inhibiting SIRT1 reversed its proliferative and anti-inflammatory effects. CONCLUSION: In vitro and in vivo, phellopterin exerts anti-inflammatory and proliferative effects that promote diabetic wound healing, and the potential mechanism depends on SIRT1.


Assuntos
Angelica , Diabetes Mellitus Experimental , Angelica/química , Animais , Anti-Inflamatórios/farmacologia , Molécula 1 de Adesão Celular , Cumarínicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Humanos , Inflamação , Molécula 1 de Adesão Intercelular , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro , Sirtuína 1/metabolismo , Estreptozocina/farmacologia , Úlcera , Cicatrização
15.
Thorac Cancer ; 13(21): 3084-3097, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36127731

RESUMO

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first "tumor agnostic" drugs approved for pan-cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second-generation drugs designed to overcome first-generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and (DNA and/or RNA-based) next-generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first- and second-generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.


Assuntos
Neoplasias , Receptor trkC , Humanos , Receptor trkC/genética , Receptor trkA/genética , Hibridização in Situ Fluorescente , Consenso , Fusão Gênica , Neoplasias/patologia
16.
BMC Complement Med Ther ; 22(1): 209, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35932049

RESUMO

BACKGROUND: The Sheng-ji Hua-yu (SJHY) formula is a quite effective Traditional Chinese Medicines (TCM) in the treatment of delayed diabetic wounds. Previous research has shown that the SJHY formula has significant anti-inflammatory and wound-healing effects, but the precise mechanism remains unknown. The purpose of this study was to evaluate the effects of rhein, a compound extracted from SJHY formula, in keratinocytes and to investigate the underlying mechanisms. METHODS: Microscale thermophoresis (MST) technology was used to confirm that rhein binds directly to oestrogen receptors (ERs). Rhein was then used to treat keratinocytes in vitro. Cell cycle and proliferation analysis, Real-time polymerase chain reaction (RT-PCR) and Western-blot were conducted. RESULTS: Rhein increased the proportion of cells in the S phase of the cell cycle and promoted keratinocyte proliferation. ICI 182,780, an ER inhibitor, was also used to treat keratinocytes. The expression of c-myc mRNA and protein induced by rhein was antagonized by ICI 182,780, indicating that this induction is ER dependent. Intervention with ICI 182,780 had no effect on the upregulation of FosB and JunD, indicating that activator protein 1 (AP-1) members (FosB and JunD) are involved in rhein-induced c-myc mRNA and protein expression but does not require the ER. CONCLUSION: The present study found that rhein stimulates keratinocyte proliferation by activating the oestrogen signalling pathway via the oestrogen receptor, which induces the expression of c-myc in collaboration with FosB and JunD, thereby accelerating the process of re-epithelialization.


Assuntos
Antraquinonas/farmacologia , Receptores de Estrogênio , Úlcera Cutânea , Proliferação de Células , Fulvestranto/metabolismo , Fulvestranto/farmacologia , Humanos , Queratinócitos/metabolismo , RNA Mensageiro/metabolismo , Receptores de Estrogênio/metabolismo , Úlcera Cutânea/metabolismo
17.
Front Pharmacol ; 13: 931495, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35814199

RESUMO

Objective: Continuous lenalidomide (LEN) therapy is important to achieve a therapeutic effect in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). However, despite dose adjustment according to kidney function, many patients discontinue LEN therapy because of hematological toxicity. To date, therapeutic drug monitoring (TDM) of LEN has not been performed in oncology, and no target concentration level has been yet defined. The aim of this study was to evaluate the exposure-safety relationship of LEN and determine the target concentration for toxicity. Materials and Methods: A prospective observational study was designed and implemented. Blood samples were collected at 0.5 h (trough concentration, Cmin) before oral administration and 1 h (C1h) thereafter on the day. Clinical data were gathered from patients' medical records and laboratory reports. Outcome measures of hematological toxicity were defined by the Common Terminology Criteria for Adverse Events. The concentration values were dichotomized by receiver operating characteristic (ROC) curve analysis, and the association between exposure and outcome was determined using the logistic regression model. Results: Out of the 61 patients enrolled in this study, 40 (65.57%) had MM, and 21 (34.43%) had NHL. Hematological toxicity was reported in 15 (24.59%) patients. The LEN Cmin showed remarkable differences (p = 0.031) among patients with or without hematological toxicity, while no association between C1h values and toxicity was noted (p>0.05). By ROC analysis, a Cmin threshold of 10.95 ng/mL was associated with the best sensitivity/specificity for toxicity events (AUC = 0.687; sensitivity = 0.40; specificity = 0.935). By multivariate logistic regression, an LEN Cmin below 10.95 ng/mL was associated with a markedly decreased risk of hematological toxicity (<10.95 ng/mL vs. >10.95 ng/mL: OR = 0.023, 95% CI = 0.002-0.269; p = 0.003). Conclusions: We demonstrate that the LEN trough concentration correlates with hematological toxicity, and the Cmin threshold for hematological toxicity (10.95 ng/mL) is proposed. Altogether, LEN TDM appears to be a new approach to improve medication safety and achieve continuous treatment for patients with NHL or MM in routine clinical care.

18.
Clin Med Insights Oncol ; 16: 11795549221109500, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35875418

RESUMO

Background: Bone-related extramedullary disease (EMD-B) is mass of clonal plasma cells derived from adjacent bone lesions and has obvious heterogeneities in clinical outcomes. This retrospective study aims to evaluate the treatment outcomes and long-term prognosis of newly diagnosed myeloma patients with EMD-B. Methods: This was a retrospective study conducted in Beijing Chaoyang Hospital from January 1, 2010 to December 31, 2019. Seventy-seven newly diagnosed multiple myeloma patients with EMD-B were selected. Propensity score matching (1:2) was used to match patients with and without EMD-B. After matching, 132 patients without extramedullary disease (non-EMD) were included in the study. All patients received bortezomib-based regimens as induction therapy. Results: After matching, baseline data of the 2 groups were comparable. The Cox regression analysis of patients with EMD-B showed that age, paravertebral lesions, and immunoglobulin D (IgD) type may have adverse effects on survival. Bone-related extramedullary disease at new diagnosis was a risk predictor of survival (hazard ration [HR] = 1.80, 95% confidence interval [CI]: 1.09-2.98, P = .022). The median survival time of the EMD-B group was significantly shorter than that of the non-EMD group (52 months vs 96 months, P = .043). Induction therapy did not show any significant differences in effectiveness between the 2 groups. Autologous stem cell transplantation (ASCT) significantly increased complete remission rate of patients with EMD-B (EMD-B vs non-EMD: no ASCT 15.7% vs 31.9%, P = .035; ASCT 42.3% vs 48.8%, P = .626) and improved their median overall survival rate (EMD-B vs non-EMD: no ASCT 49 months vs 75 months, P = .003; ASCT not reached vs 96 months, P = .505). Conclusions: This study demonstrated that newly diagnosed myeloma patients with EMD-B had poor outcomes, which could be improved by ASCT.

19.
Front Oncol ; 12: 922039, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35865475

RESUMO

Objective: To use machine learning methods to explore overall survival (OS)-related prognostic factors in elderly multiple myeloma (MM) patients. Methods: Data were cleaned and imputed using simple imputation methods. Two data resampling methods were implemented to facilitate model building and cross validation. Four algorithms including the cox proportional hazards model (CPH); DeepSurv; DeepHit; and the random survival forest (RSF) were applied to incorporate 30 parameters, such as baseline data, genetic abnormalities and treatment options, to construct a prognostic model for OS prediction in 338 elderly MM patients (>65 years old) from four hospitals in Beijing. The C-index and the integrated Brier score (IBwere used to evaluate model performances. Results: The 30 variables incorporated in the models comprised MM baseline data, induction treatment data and maintenance therapy data. The variable importance test showed that the OS predictions were largely affected by the maintenance schema variable. Visualizing the survival curves by maintenance schema, we realized that the immunomodulator group had the best survival rate. C-indexes of 0.769, 0.780, 0.785, 0.798 and IBS score of 0.142, 0.112, 0.108, 0.099 were obtained from the CPH model, DeepSurv, DeepHit, and the RSF model respectively. The RSF model yield best scores from the fivefold cross-validation, and the results showed that different data resampling methods did affect our model results. Conclusion: We established an OS model for elderly MM patients without genomic data based on 30 characteristics and treatment data by machine learning.

20.
Comput Biol Med ; 148: 105873, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35868043

RESUMO

Neuroprotective therapy after ischemic stroke remains a significant need, but current measures are still insufficient. The Fu-Fang-Dan-Zhi tablet (FFDZT) is a proprietary Chinese medicine clinically employed to treat ischemic stroke in the recovery period. This work aims to systematically investigate the neuroprotective mechanism of FFDZT. A systems strategy that integrated metabolomics, transcriptomics, network pharmacology, and in vivo and in vitro experiments was used. First, middle cerebral artery occlusion (MCAO) model rats were treated with FFDZT. FFDZT treatment significantly reduced the infarct volume in the brains of middle cerebral artery occlusion (MCAO) model rats. Then, samples of serum and brain tissue were taken for metabolomics and transcriptomics studies, respectively; gene expression profiles of MCF7 cells treated with FFDZT and its 4 active compounds (senkyunolide I, formononetin, drilodefensin, and tanshinone IIA) were produced for CMAP analysis. Computational analysis of metabolomics and transcriptomics results suggested that FFDZT regulated glutamate and oxidative stress-related metabolites (2-hydroxybutanoic acid and 2-hydroxyglutaric acid), glutamate receptors (NMDAR, KA, and AMPA), glutamate involved pathways (glutamatergic synapse pathway; d-glutamine and d-glutamate metabolism; alanine, aspartate and glutamate metabolism), as well as the reactive oxygen species metabolic process. CMAP analysis indicated that two active ingredients of FFDZT (tanshinone ⅡA and senkyunolide I) could act as glutamate receptor antagonists. Next, putative therapeutic targets of FFDZT's active ingredients identified in the brain were collected from multiple resources and filtered by statistical criteria and tissue expression information. Network pharmacological analysis revealed extensive interactions between FFDZT's putative targets, anti-IS drug targets, and glutamate-related enzymes, while the resulting PPI network exhibited modular topology. The targets in two of the modules were significantly enriched in the glutamatergic synapse pathway. The interactions between FFDZT's ingredients and important targets were verified by molecular docking. Finally, in vitro experiments validated the effects of FFDZT and its ingredients in suppressing glutamate-induced PC12 cell injury and reducing the generation of reactive oxygen species. All of our findings indicated that FFDZT's efficacy for treating ischemic stroke could be due to its neuroprotection against glutamate-induced oxidative cell death.


Assuntos
Medicamentos de Ervas Chinesas , AVC Isquêmico , Animais , Morte Celular , Ácido Glutâmico , Infarto da Artéria Cerebral Média , Simulação de Acoplamento Molecular , Neuroproteção , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio , Comprimidos
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