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The treatment of erectile dysfunction (ED) using penile prosthesis implantation (PPI) has recently garnered significant interest, but reports of bibliometric analyses of studies on PPI have yet to appear. Therefore, the purpose of this study is to use visualization techniques to statistically and qualitatively assess the state of knowledge, current research topics, and trends in this field. The Science Citation Index-Expanded (SCI-E) from the Web of Science Core Collection (WoSCC) was searched for publications about PPI from the inception of the database to 2023. VOSviewer (version 1.6.19), CiteSpace (version 6.2. R2), and Excel (version 2021) were used for the data analysis. The results show a total of 1015 original articles and reviews on PPI published over this nearly 50 years, with an increasing trend in the number of studies published each year. The United States is the country with the most published studies (n = 578). Mayo Clinic is the organization with the most publications overall (n = 46). The Journal of Sexual Medicine has the most publications (n = 184). The most prolific author is Wilson, Steven K (n = 31). The most commonly used terms were erectile dysfunction (n = 509), penile prosthesis (n = 332), implantation (n = 207), satisfaction (n = 201), surgery (n = 200), infection (n = 134), outcomes (n = 128), Peyronie's disease (n = 121), men (n = 115), and experience (n = 109). Current research focuses on four main areas: complications of PPI, the current status of inflatable penile prosthesis (IPP), the use of PPI in radical prostatectomy and Peyronie's disease populations, and patient satisfaction after PPI. Improving patient satisfaction with PPI through improved mechanical design and surgical techniques is a key concern for future research.
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BACKGROUND: The feasibility and safety of enhanced recovery after surgery (ERAS) for percutaneous computed tomography (CT)-guided microwave ablation (MWA) for treating lung nodules remain unclear. METHODS AND MATERIALS: A total of 409 patients with lung tumors treated at the Department of Thoracic Surgery, First Affiliated Hospital of Guangxi Medical University from August 2020 to May 2023 were enrolled. Perioperative data, including baseline characteristics, operation time, postoperative pain score (visual analog scale [VAS]), hospitalization expenses, postoperative complications, total hospital stay, and patient satisfaction, were observed and recorded. RESULTS: No perioperative mortality occurred in either group and complete ablation was achieved in all patients. Patients in the ERAS group had significantly shorter hospital stays (P < 0.001), reduced operation times (P = 0.047), lower hospitalization expenses (P < 0.001), lower VAS scores (P < 0.001), and fewer complications (P = 0.047) compared with the traditional group. CONCLUSIONS: ERAS for percutaneous CT-guided MWA (ERAA) is safe, effective, and feasible for the treatment of lung nodules.
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Recuperação Pós-Cirúrgica Melhorada , Neoplasias Pulmonares , Micro-Ondas , Tomografia Computadorizada por Raios X , Humanos , Masculino , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Feminino , Micro-Ondas/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Idoso , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Tempo de Internação/estatística & dados numéricos , Cirurgia Assistida por Computador/métodos , Resultado do Tratamento , Ablação por Radiofrequência/métodos , Ablação por Radiofrequência/efeitos adversos , Adulto , Estudos de Viabilidade , Duração da CirurgiaRESUMO
During myocardial injury, inflammatory mediators and oxidative stress significantly increase to impair cardiac mitochondria. Emerging evidence has highlighted interplays between circadian protein-period 2 (Per2) and mitochondrial metabolism. However, besides circadian rhythm regulation, the direct role of Per2 in mitochondrial performance particularly following acute stress, remains unknown. In this study, we aim to determine the importance of Per2 protein's regulatory role in mitochondrial function following exposure to inflammatory cytokine TNFα and oxidative stressor H2O2 in human cardiomyocytes. Global warm ischemia (37 °C) significantly impaired complex I activity with concurrently reduced mitochondrial Per2 in adult mouse hearts. TNFα or H2O2 decreased Per2 protein levels and damaged mitochondrial respiratory function in adult mouse cardiomyocytes. Next, mitochondrial membrane potential ([Formula: see text] M) using JC-1 fluorescence probe and mitochondrial respiration capacity via Seahorse Cell Mito Stress Test were then detected in Per2 or control siRNA transfected AC16 Human Cardiomyocytes (HCM) that were subjected to 2 h-treatment of TNFα (100 ng/ml) or H2O2 (100 µM). After 4 h-treatment, cell death was also measured using Annexin V and propidium iodide apoptosis kit through flow cytometry. We found that knockdown of Per2 enhanced TNFα-induced cell death and TNFα- or H2O2-disrupted [Formula: see text]M, as well as TNFα- or H2O2-impaired mitochondrial respiration function. In conclusion, Per2 knockdown increases likelihood of cell death and mitochondrial dysfunction in human cardiomyocytes exposed to either TNFα or H2O2, supporting the protective role of Per2 in HCM during stress with a focus on mitochondrial function.
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Peróxido de Hidrogênio , Fator de Necrose Tumoral alfa , Animais , Humanos , Camundongos , Apoptose , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/metabolismo , Potencial da Membrana Mitocondrial , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Proteínas Circadianas Period/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Lymph node metastasis (LNM) is an essential factor affecting the prognosis of patients with lung squamous cell carcinoma (LUSC), as well as a critical consideration for the choice of treatment strategy. Exploring effective methods for predicting LNM in LUSC may benefit clinical decision making. MATERIALS AND METHODS: We used data collected from the Surveillance, Epidemiology, and End Results (SEER) database to develop machine learning algorithm classifiers, including boosted trees (BTs), based on the primary clinical parameters of patients to predict LNM in LUSC. Training on a large-sample training cohort (n = 8,063) allowed for the construction of several concise classifiers for LNM prediction in LUSC, which were then validated using test and in-house cohorts (n = 2,017 and 57, respectively). RESULTS: The six classifiers established in this research enabled distinction between patients with and without LNM. Among these classifiers, the BT classifier was the top performer, with accuracy, F1 scores, precision, recall, sensitivity, and specificity values of 0.654, 0.621, 0.654, 0.592, 0.592, and 0.711, respectively. The precision recall (PR) and receiver operating characteristic (ROC) (with area under the curve = 0.714) curves also supported this result, which was validated by the in-house cohort. Notably, the tumor stage was a critical factor in determining LNM in patients with LUSC. CONCLUSIONS: The use of classifiers, especially the BT classifier, may serve as a useful tool for improving clinical precision and individualized treatment of patients with LUSC.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Metástase Linfática/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Aprendizado de Máquina , Algoritmos , Pulmão/patologia , Linfonodos/patologiaRESUMO
Mesenchymal stem cell (MSC)-based therapy is one of the most promising modalities for cardiac repair. Accumulated evidence suggests that the therapeutic value of MSCs is mainly attributable to exosomes. MSC-derived exosomes (MSC-Exos) replicate the beneficial effects of MSCs by regulating various cellular responses and signaling pathways implicated in cardiac regeneration and repair. miRNAs constitute an important fraction of exosome content and are key contributors to the biological function of MSC-Exo. MSC-Exo carrying specific miRNAs provides anti-apoptotic, anti-inflammatory, anti-fibrotic, and angiogenic effects within the infarcted heart. Studying exosomal miRNAs will provide an important insight into the molecular mechanisms of MSC-Exo in cardiac regeneration and repair. This significant information can help optimize cell-free treatment and overcome the challenges associated with MSC-Exo therapeutic application. In this review, we summarize the characteristics and the potential mechanisms of MSC-derived exosomal miRNAs in cardiac repair and regeneration.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , MicroRNAs , Infarto do Miocárdio , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Coração , Células-Tronco Mesenquimais/metabolismoRESUMO
Natural products, and especially the active ingredients found in traditional Chinese medicine (TCM), have a thousand-year-long history of clinical use and a strong theoretical basis in TCM. As such, traditional remedies provide shortcuts for the development of original new drugs in China, and increasing numbers of natural products are showing great therapeutic potential in various diseases. This paper reviews the molecular mechanisms of action of natural products from different sources used in the treatment of inflammatory diseases and cancer, introduces the methods and newly emerging technologies used to identify and validate the targets of natural active ingredients, enumerates the expansive list of TCM used to treat inflammatory diseases and cancer, and summarizes the patterns of action of emerging technologies such as single-cell multiomics, network pharmacology, and artificial intelligence in the pharmacological studies of natural products to provide insights for the development of innovative natural product-based drugs. Our hope is that we can make use of advances in target identification and single-cell multiomics to obtain a deeper understanding of actions of mechanisms of natural products that will allow innovation and revitalization of TCM and its swift industrialization and internationalization.
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Musculoskeletal diseases such as muscular dystrophy, cachexia, osteoarthritis, and rheumatoid arthritis impair overall physical health and reduce survival. Patients suffer from pain, dysfunction, and dysmobility due to inflammation and fibrosis in bones, muscles, and joints, both locally and systemically. The Interleukin-6 (IL-6) family of cytokines, most notably IL-6, is implicated in musculoskeletal disorders and cachexia. Here we show elevated circulating levels of OSM in murine pancreatic cancer cachexia and evaluate the effects of the IL-6 family member, Oncostatin M (OSM), on muscle and bone using adeno-associated virus (AAV) mediated over-expression of murine OSM in wildtype and IL-6 deficient mice. Initial studies with high titer AAV-OSM injection yielded high circulating OSM and IL-6, thrombocytosis, inflammation, and 60% mortality without muscle loss within 4 days. Subsequently, to mimic OSM levels in cachexia, a lower titer of AAV-OSM was used in wildtype and Il6 null mice, observing effects out to 4 weeks and 12 weeks. AAV-OSM caused muscle atrophy and fibrosis in the gastrocnemius, tibialis anterior, and quadriceps of the injected limb, but these effects were not observed on the non-injected side. In contrast, OSM induced both local and distant trabecular bone loss as shown by reduced bone volume, trabecular number, and thickness, and increased trabecular separation. OSM caused cardiac dysfunction including reduced ejection fraction and reduced fractional shortening. RNA-sequencing of cardiac muscle revealed upregulation of genes related to inflammation and fibrosis. None of these effects were different in IL-6 knockout mice. Thus, OSM induces local muscle atrophy, systemic bone loss, tissue fibrosis, and cardiac dysfunction independently of IL-6, suggesting a role for OSM in musculoskeletal conditions with these characteristics, including cancer cachexia.
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Cardiopatias , Interleucina-6 , Animais , Caquexia , Fibrose , Inflamação , Interleucina-6/farmacologia , Camundongos , Camundongos Knockout , Atrofia Muscular , Oncostatina M/farmacologia , RNARESUMO
Cardiac dysfunction/damage following trauma, shock, sepsis, and ischemia impacts clinical outcomes. Acute inflammation and oxidative stress triggered by these injuries impair mitochondria, which are critical to maintaining cardiac function. Despite sex dimorphisms in consequences of these injuries, it is unclear whether mitochondrial bioenergetic responses to inflammation/oxidative stress are sex-dependent. We hypothesized that sex disparity in mitochondrial bioenergetics following TNFα or H2O2 exposure is responsible for reported sex differences in cardiac damage/dysfunction. Methods and Results: Cardiomyocytes isolated from age-matched adult male and female mice were subjected to 1 h TNFα or H2O2 challenge, followed by detection of mitochondrial respiration capacity using the Seahorse XF96 Cell Mito Stress Test. Mitochondrial membrane potential (ΔΨm) was analyzed using JC-1 in TNFα-challenged cardiomyocytes. We found that cardiomyocytes isolated from female mice displayed a better mitochondrial bioenergetic response to TNFα or H2O2 than those isolated from male mice did. TNFα decreased ΔΨm in cardiomyocytes isolated from males but not from females. 17ß-estradiol (E2) treatment improved mitochondrial metabolic function in cardiomyocytes from male mice subjected to TNFα or H2O2 treatment. Conclusions: Cardiomyocyte mitochondria from female mice were more resistant to acute stress than those from males. The female sex hormone E2 treatment protected cardiac mitochondria against acute inflammatory and oxidative stress.
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Metabolismo Energético , Mitocôndrias Cardíacas , Fatores Sexuais , Fator de Necrose Tumoral alfa , Animais , Feminino , Peróxido de Hidrogênio/metabolismo , Inflamação/metabolismo , Masculino , Camundongos , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
SHP2 is the first oncogenic tyrosine phosphatase encoded by PTPN11, which plays a significant regulatory role in cancer and inflammation-related diseases. Although SHP2 allosteric inhibitors have been used in phase I/II clinical trials for solid tumors, whether SHP2 inhibition alleviates psoriasis remains unclear. Here we expressed and purified SHP2 related proteins, and established an enzyme activity screening system for different conformations of SHP2. We launched an iterative medicinal chemistry program and identified the lead compound, TK-453. Importantly, TK-453 possessed stronger affinity with SHP2 than SHP099, evidenced by the cocrystal structure of SHP2/TK-453, revealing that the additional aryl-S-aryl bridge in TK-453 induces a 1.8 Å shift of the dichlorophenyl ring and an approximate 20° deviation of the pyrazine ring plane relative to SHP099. Furthermore, TK-453 significantly ameliorated imiquimod-triggered skin inflammation in mice via inhibition of the IL-23/Th17 axis, proving that SHP2 is a potential therapeutic target for psoriasis.
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BACKGROUND: Heart transplantation, a life-saving approach for patients with end-stage heart disease, is limited by shortage of donor organs. While prolonged storage provides more organs, it increases the extent of ischemia. Therefore, we seek to understand molecular mechanisms underlying pathophysiological changes of donor hearts during prolonged storage. Additionally, considering mesenchymal stromal cell (MSC)-derived paracrine protection, we aim to test if MSC secretome preserves myocardial transcriptome profile and whether MSC secretome from a certain source provides the optimal protection in donor hearts during cold storage. METHODS AND RESULTS: Isolated mouse hearts were divided into: no cold storage (control), 6 h cold storage (6 h-I), 6 h-I + conditioned media from bone marrow MSCs (BM-MSC CM), and 6 h-I + adipose-MSC CM (Ad-MSC CM). Deep RNA sequencing analysis revealed that compared to control, 6 h-I led to 266 differentially expressed genes, many of which were implicated in modulating mitochondrial performance, oxidative stress response, myocardial function, and apoptosis. BM-MSC CM and Ad-MSC CM restored these gene expression towards control. They also improved 6 h-I-induced myocardial functional depression, reduced inflammatory cytokine production, decreased apoptosis, and reduced myocardial H2O2. However, neither MSC-exosomes nor exosome-depleted CM recapitulated MSC CM-ameliorated apoptosis and CM-improved mitochondrial preservation during cold ischemia. Knockdown of Per2 by specific siRNA abolished MSC CM-mediated these protective effects in cardiomyocytes following 6 h cold storage. CONCLUSIONS: Our results demonstrated that using MSC secretome (BM-MSCs and Ad-MSCs) during prolonged cold storage confers preservation of the normal transcriptional "fingerprint", and reduces donor heart damage. MSC-released soluble factors and exosomes may synergistically act for donor heart protection.
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Transplante de Coração , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Medula Óssea , Humanos , Peróxido de Hidrogênio/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Secretoma , Doadores de Tecidos , TranscriptomaRESUMO
INTRODUCTION: Isoflurane inhalation leads to apoptotic neurodegeneration and further results in learning and cognitive dysfunction. Notoginsenoside R1 (NGR1), a major ingredient from Radix notoginseng, has been reported to exert neuroprotective effect during brain or neuron injury. This study aimed to investigate the effect of NGR1 on neurological impairment. METHODS: Sixty-four male Sprague Dawley rat pups (15-20 g) of postnatal day 7 were recruited. Spatial learning and memory were assessed by the Morris water maze test, and the neurological severity score was determined. Real-time quantitative PCR was used to detect the expression levels of microRNA (miR)-29a. Enzyme-linked immunosorbent assay was applied to estimate the levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampal tissues. RESULTS: NGR1 attenuated neurological impairment induced by isoflurane, shown by the decrease in neurological function score and escape latency and the increase in staying time in the original quadrant in rats. NGR1 reversed the downregulation of miR-29a expression induced by isoflurane treatment. After the treatment of NGR1, the elevated levels of IL-6, TNF-α, and IL-1ß induced by isoflurane were all decreased significantly in the hippocampal tissues of rats. Additionally, the repressive action of NGR1 in neurological impairment and neuroinflammation was eliminated by downregulating miR-29a in rats. CONCLUSION: NGR1 protects against isoflurane-induced neurological impairment. The protective effect of NGR1 might be achieved by promoting the expression of miR-29a and preventing inflammatory response.
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Ginsenosídeos/uso terapêutico , Isoflurano , MicroRNAs , Doenças Neuroinflamatórias/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Isoflurano/toxicidade , Masculino , MicroRNAs/genética , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: Heart transplantation is the gold standard of treatments for end-stage heart failure, but its use is limited by extreme shortage of donor organs. The time "window" between procurement and transplantation sets the stage for myocardial ischemia/reperfusion injury, which constrains the maximal storage time and lowers use of donor organs. Given mesenchymal stem cell (MSC)-derived paracrine protection, we aimed to evaluate the efficacy of MSC-conditioned medium (CM) and extracellular vesicles (EVs) when added to ex vivo preservation solution on ameliorating ischemia/reperfusion-induced myocardial damage in donor hearts. METHODS: Mouse donor hearts were stored at 0°C-4°C of <1-hour cold ischemia (<1hr-I), 6hr-I + vehicle, 6hr-I + MSC-CM, 6hr-I + MSC-EVs, and 6hr-I + MSC-CM from MSCs treated with exosome release inhibitor. The hearts were then heterotopically implanted into recipient mice. At 24 hours postsurgery, myocardial function was evaluated. Heart tissue was collected for analysis of histology, apoptotic cell death, microRNA (miR)-199a-3p expression, and myocardial cytokine production. RESULTS: Six-hour cold ischemia significantly impaired myocardial function, increased cell death, and reduced miR-199a-3p in implanted hearts versus <1hr-I. MSC-CM or MSC-EVs in preservation solution reversed the detrimental effects of prolong cold ischemia on donor hearts. Exosome-depleted MSC-CM partially abolished MSC secretome-mediated cardioprotection in implanted hearts. MiR-199a-3p was highly enriched in MSC-EVs. MSC-CM and MSC-EVs increased cold ischemia-downregulated miR-199a-3p in donor hearts, whereas exosome-depletion neutralized this effect. CONCLUSIONS: MSC-CM and MSC-EVs confer improved myocardial preservation in donor hearts during prolonged cold static storage and MSC-EVs can be used for intercellular transport of miRNAs in heart transplantation.
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Criopreservação , Vesículas Extracelulares , Transplante de Coração , Células-Tronco Mesenquimais , Soluções para Preservação de Órgãos , Animais , Isquemia Fria , Meios de Cultivo Condicionados , Regulação para Baixo , Vesículas Extracelulares/metabolismo , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Doadores de TecidosRESUMO
As a cytoplasmic sensor of double-stranded DNA (dsDNA), the cyclic GMP-AMP synthase-stimulator of IFN genes (STING) pathway plays an important role in antitumor immunity. In this study, we investigated the effect of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) on tumor cell-intrinsic STING pathway activity and DNA repair in colon cancer. SHP2 interacted with and dephosphorylated PARP1 after DNA damage. PARP1 inhibition by SHP2 resulted in reduced DNA repair and accumulation of dsDNA in cells, thus promoting hyperactivation of the STING pathway. The SHP2 agonist lovastatin was able to enhance SHP2 activity and promote STING pathway activation. Moreover, lovastatin significantly enhanced the efficacy of chemotherapy in colon cancer models, in part via STING pathway-mediated antitumor immunity. These findings suggest that SHP2 exacerbates STING pathway activation by restricting PARP1-mediated DNA repair in tumor cells, providing a basis for the combined use of lovastatin and chemotherapy in the treatment of colon cancer. SIGNIFICANCE: Dephosphorylation of PARP1 by SHP2 simultaneously suppresses DNA repair and enhances STING pathway-mediated antitumor immunity, highlighting SHP2 activation as a potential therapeutic approach in colon cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Colo/tratamento farmacológico , Reparo do DNA , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Animais , Apoptose , Ciclo Celular , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Dano ao DNA , Feminino , Humanos , Irinotecano/administração & dosagem , Lovastatina/administração & dosagem , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nucleotidiltransferases/genética , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure-activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties.
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Exploring the underlying mechanisms of cancer development is useful for cancer treatment. In this paper, we analyzed the transcriptome profiles from the human normal pancreas, pancreatitis, pancreatic cancer and metastatic pancreatic cancer to study the intricate associations among pancreatic cancer progression. We clustered the transcriptome data, and analyzed the differential expressed genes. WGCNA was applied to construct co-expression networks and detect important modules. Importantly we selected the module in a different way. As the pancreatic disease deteriorates, the number of differentially expressed genes increases. The gene networks of T cells and interferon are upregulated in stages. In conclusion, the network-based study provides gradually activated gene networks in the disease progression of pancreatitis, pancreatic cancer, and metastatic pancreatic cancer. It may contribute to the rational design of anti-cancer drugs.
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Perfilação da Expressão Gênica , Neoplasias Pancreáticas/metabolismo , Pancreatite Crônica/metabolismo , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Pancreatite Crônica/tratamento farmacológico , Pancreatite Crônica/genética , Pancreatite Crônica/patologiaRESUMO
Heart transplantation is a life-saving therapy for end-stage organ failure. Organ deterioration during transportation limits storage to 4 hours, limiting hearts available. Approaches ameliorating organ damage could increase the number of hearts acceptable for transplantation. Prior studies show that adipose-derived stem/stromal cell secretome (ASC-S) rescues tissues from postischemic damage in vivo. This study tested whether ASC-S preserved the function of mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes (iCM) exposed to organ transportation and transplantation conditions. Hearts were subjected to cold University of Wisconsin (UW) cardioplegic solution ± ASC-S for 6 hours followed by analysis using the Langendorff technique. In parallel, the effects of ASC-S on the recovery of iCM from UW solution were examined when provided either during or after cold cardioplegia. Exposure of hearts and iCM to UW deteriorated contractile activity and caused cell apoptosis, worsening in iCM as a function of exposure time; these were ameliorated by augmenting with ASC-S. Silencing of superoxide dismutase 3 and catalase expression prior to secretome generation compromised the ASC-S cardiomyocyte-protective effects. In this study, a novel in vitro iCM model was developed to complement a rodent heart model in assessing efficacy of approaches to improve cardiac preservation. ASC-S displays strong cardioprotective activity on iCM either with or following cold cardioplegia. This effect is associated with ASC-S-mediated cellular clearance of reactive oxygen species. The effect of ASC-S on the temporal recovery of iCM function supports the possibility of lengthening heart storage by augmenting cardioplegic transport solution with ASC-S, expanding the pool of hearts for transplantation.
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Soluções Cardioplégicas/toxicidade , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Miócitos Cardíacos/metabolismo , Soluções para Preservação de Órgãos/toxicidade , Recuperação de Função Fisiológica/fisiologia , Adenosina/toxicidade , Alopurinol/toxicidade , Animais , Glutationa/toxicidade , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Insulina/toxicidade , Preparação de Coração Isolado/métodos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Rafinose/toxicidade , Recuperação de Função Fisiológica/efeitos dos fármacosRESUMO
Gastrodia elata and Ligusticum chuanxiong are used to treat primary headaches for many years. Gastrodin (GAS) and tetramethylpyrazine (TMP)/ferulic acid (FA) are the main active ingredients of Gastrodia elata and Ligusticum chuanxiong, respectively. Previous studies demonstrated the pharmacokinetics of GAS, TMP, and FA in the blood and brain interstitial fluids (BIF) in healthy animals but not in animal model with liver-yang hyperactivity migraine. Hence, this study examined the pharmacokinetics of GAS after its oral administration in the presence of different concentrations of TMP and FA in animals with liver-yang migraine hyperactivity. In the control group, GAS was administrated without TMP and FA. Pharmacokinetic parameters were determined using the blood-brain microdialysis in combination with the high-performance liquid chromatography method. Results revealed that the maximum drug concentrations (Cmax) in the serum, area under curve (AUC), and mean residence time (MRT) of GAS decreased in normal animals, whereas Cmax increased significantly in model animals. These findings indicate that varying concentrations of TMP and FA play an important role in the pharmacokinetics of GAS in both normal and migraine model animals, validating the utility of the ancient formulation.
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Transtornos de Enxaqueca , Animais , Álcoois Benzílicos , Encéfalo , Ácidos Cumáricos , Glucosídeos , Fígado , Microdiálise , Transtornos de Enxaqueca/tratamento farmacológico , PirazinasRESUMO
Microplastics pollution presents an increasing concern worldwide due to the large amount and potential risks. However, data on microplastics in the freshwater environment are still limited, especially in southwest China. This study investigated the microplastics distribution, characteristics and risks in urban water of different cities in the Tuojiang River basin in southwest China. Microplastics were found in all seven cities of the Tuojiang River basin and the concentrations varied from 911.57 ± 199.73 to 3395.27 ± 707.22 items/m3, among which Ziyang urban water had the highest microplastics concentration. Fiber (34.88-65.85%) was a typical and abundant microplastic type. The small size (0.5-1 mm) (27.27-66.67%) was predominant, and white (23.30-54.29%) was the dominant color among all samples. Polypropylene was identified as the main polymer type by Fourier transform infrared spectroscopy. The morphological analysis by scanning electron microscopy indicated that the surfaces of the microplastics had many cracks and a multitude of particles were adsorbed onto it. According to correlation analysis, there was a significant positive correlation between gross domestic product(P=0.015<0.05) and gross domestic product of the secondary industries(P=0.014<0.05) of cities in the Tuojiang River basin and microplastics concentrations, demonstrating impacts of the secondary industries on the microplastics pollution. In addition, water bodies with lower oxidation-reduction potential tended to have higher microplastics abundance. In the Tuojiang River basin, microplastics pollution was more serious in location where water quality was poor. The polymer risk index (H) was calculated to assess the environmental risk of microplastics in different cities, and the results showed that Fushun sites had the highest risk in regard to microplastics. This study provides a valuable reference for a better understanding of the microplastics level and source identification in southwest China.
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Rios , Poluentes Químicos da Água , China , Cidades , Monitoramento Ambiental , Microplásticos , Plásticos , Poluentes Químicos da Água/análiseRESUMO
Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.
Assuntos
Gorduras na Dieta/efeitos adversos , Fígado Gorduroso , Resistência à Insulina , Interleucina-18/metabolismo , Macrófagos/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Animais , Gorduras na Dieta/farmacologia , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Interleucina-18/genética , Macrófagos/patologia , Camundongos , Camundongos Knockout , Proteína Tirosina Fosfatase não Receptora Tipo 11/genéticaRESUMO
Preserving mitochondrial activity is crucial in rescuing cardiac function following acute myocardial ischemia/reperfusion (I/R). The sex difference in myocardial functional recovery has been observed after I/R. Given the key role of mitochondrial connexin43 (Cx43) in cardiac protection initiated by ischemic preconditioning, we aimed to determine the implication of mitochondrial Cx43 in sex-related myocardial responses and to examine the effect of estrogen (17ß-estradiol, E2) on Cx43, particularly mitochondrial Cx43-involved cardiac protection following I/R. Mouse primary cardiomyocytes and isolated mouse hearts (from males, females, ovariectomized females, and doxycycline-inducible Tnnt2-controlled Cx43 knockout without or with acute post-ischemic E2 treatment) were subjected to simulated I/R in culture or Langendorff I/R (25-min warm ischemia/40-min reperfusion), respectively. Mitochondrial membrane potential and mitochondrial superoxide production were measured in cardiomyocytes. Myocardial function and infarct size were determined. Cx43 and its isoform, Gja1-20k, were assessed in mitochondria. Immunoelectron microscopy and co-immunoprecipitation were also used to examine mitochondrial Cx43 and its interaction with estrogen receptor-α by E2 in mitochondria, respectively. There were sex disparities in stress-induced cardiomyocyte mitochondrial function. E2 partially restored mitochondrial activity in cardiomyocytes following acute injury. Post-ischemia infusion of E2 improved functional recovery and reduced infarct size with increased Cx43 content and phosphorylation in mitochondria. Ablation of cardiac Cx43 aggravated mitochondrial damage and abolished E2-mediated cardiac protection during I/R. Female mice were more resistant to myocardial I/R than age-matched males with greater protective role of mitochondrial Cx43 in female hearts. Post-ischemic E2 usage augmented mitochondrial Cx43 content and phosphorylation, increased mitochondrial Gja1-20k, and showed cardiac protection.