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Background and aims: In all age, FoShou as a Chinese medicinal herb has been active in various kinds of Traditional Chinese medicine formula to treating diabetes. Hesperidin (HES), the main monomeric component of FoShou, has been extensively investigated for interventions with pathogenic mechanism of diabetes as well as subsequent treatment of associated complications. Islet ß-cells have an essential effect on dynamically regulating blood sugar. Functional abnormalities in these cells and their death are strongly associated with the onset of diabetes. Therefore, induction of islet endocrine cell lineage re-editing for damaged ßcell replenishment would be a promising therapeutic tool. Previously, it has been found that HES can protect islet ß-cells in vivo, But, the regenerative function of HES in islet ß cells and its role in promoting differential non-ß cells transdifferentiation into ß cells and cell fate rewriting associated mechanisms remain unclear.This work focused on investigating whether HES can induce islet α cells transdifferentiation into ß cells for achieving damaged ß cell regeneration and the causes and possible mechanisms involved in the process. Materials and methods: In brief, 60 mg/kg/d streptozotocin (STZ) was administered intraperitoneally in each male C57bL/6J mouse raised by the high-sugar and high-fat diet (HFD) to create a diabetic mouse model with severe ß-cell damage. After 28 consecutive days of HES treatment (160 mg/kg; 320 mg/kg; once daily, as appropriate). Tracing the dynamics of α as well as ß cell transformation, together with ß cells growth and apoptosis levels during treatment by cell lineage tracing. The self-enforcing transcriptional network on which the cell lineage is based is used as a clue to explore the underlying mechanisms. Guangdong Pharmaceutical University's Animal Experiment Ethics Committee (GDPulac2019180) approved all animal experiments. Results: Localization by cell lineage we find that transdifferentiated newborn ß-cells derived from α cells appeared in the islet endocrine cell mass of DM mice under HES'action. Compared to the model group, expressed by Tunel staining and CXCL10 levels the overall apoptosis rate of ß-cells of the pancreas were reduced,the inflammatory infiltration feedback from HE staining were lower.Ki-67 positive cells showed enhanced ß-cell proliferation. Decreased HbA1c and blood glucose contents, elevated C-Peptide and insulin contents which respond to ability of nascent beta cells. Also upregulated the mRNA levels of MafA, Ngn3, PDX-1, Pax4 and Arx. Moreover, increased the expression of TGR5/cAMP-CREB/GLP-1 in mouse intestinal tissues and GLP-1/GLP-1R and cAMP-CREB/IRS2/PDX-1 in pancreatic tissues. Conclusions: HES directly affects ß-cells, apart from being anti-apoptotic and reducing inflammatory infiltration. HES promotes GLP-1 release by intestinal L cells by activating the TGR5 receptor in DM mouse and regulating its response element CREB signaling. GLP-1 then uses the GLP-1/GLP-1R system to act on IRS2, IRS2 as a port to influence α precursor cells to express PDX-1, with the mobilization of Pax4 strong expression than Arx so that α cell lineage is finally reversed for achieving ß cell endogenous proliferation.
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AIM: Diabetic cognitive impairment (DCI), considered one of the most severe and commonly overlooked complications of diabetes, has shown inconsistent findings regarding the metabolic profiles in DCI patients. This systematic review and meta-analysis aimed to identify dysregulated metabolites as potential biomarkers for early DCI, providing valuable insights into the underlying pathophysiological mechanisms. MATERIALS AND METHODS: A systematic search of four databases, namely PubMed, Embase, Web of Science and Cochrane, was conducted up to March 2024. Subsequently, a qualitative review of clinical studies was performed followed by a meta-analysis of metabolite markers. Finally, the sources of heterogeneity were explored through subgroup and sensitivity analyses. RESULTS: A total of 774 unique publications involving 4357 participants and the identification of multiple metabolites were retrieved. Of these, 13 clinical studies reported metabolite differences between the DCI and control groups. Meta-analysis was conducted for six brain metabolites and two metabolite ratios. The results revealed a significant increase in myo-inositol (MI) concentration and decreases in glutamate (Glu), Glx (glutamate and glutamine) and N-acetylaspartate/creatine (NAA/Cr) ratios in DCI, which have been identified as the most sensitive metabolic biomarkers for evaluating DCI progression. Notably, brain metabolic changes associated with cognitive impairment are more pronounced in type 2 diabetes mellitus than in type 1 diabetes mellitus, and the hippocampus emerged as the most sensitive brain region regarding metabolic changes associated with DCI. CONCLUSIONS: Our results suggest that MI, Glu, and Glx concentrations and NAA/Cr ratios within the hippocampus may serve as metabolic biomarkers for patients with early-stage DCI.
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Tumor hyperthermia is the fifth tumor treatment method after surgery, chemotherapy, radiotherapy and biological therapy, and is also one of the important adjuvant treatment methods for tumors. Hyperthermia can not only directly eliminate tumor cells, but also stimulate the antitumor immune response of the body, and improve the sensitivity of tumor tissues to radiotherapy and chemotherapy. An organoid is a tissue-specific cell cluster formed by 3D culture of various types of cells derived from target organ stem cells, which can reproduce the functions of target organs in vivo. At present, the research models of hepatocellular carcinoma (HCC) in vitro are mainly 2D culture cell line models, and there is no clinical report on tumor hyperthermia using HCC tumoroids. It was hypothesized that this will be a promising research direction.
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PURPOSE: Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed. RESULTS: In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion. CONCLUSIONS: Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.
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Antineoplásicos , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/patología , Antígeno Prostático Específico , Semivida , Resultado del Tratamiento , Antineoplásicos/uso terapéutico , Antagonistas de Receptores Androgénicos/uso terapéutico , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Obesity, a condition associated with the development of widespread cardiovascular disease, metabolic disorders, and other health complications, has emerged as a significant global health issue. Oleanolic acid (OA), a pentacyclic triterpenoid compound that is widely distributed in various natural plants, has demonstrated potential anti-inflammatory and anti-atherosclerotic properties. However, the mechanism by which OA fights obesity has not been well studied. METHOD: Network pharmacology was utilized to search for potential targets and pathways of OA against obesity. Molecular docking and molecular dynamics simulations were utilized to validate the interaction of OA with core targets, and an animal model of obesity induced by high-fat eating was then employed to confirm the most central of these targets. RESULTS: The network pharmacology study thoroughly examined 42 important OA targets for the treatment of obesity. The key biological processes (BP), cellular components (CC), and molecular functions (MF) of OA for anti-obesity were identified using GO enrichment analysis, including intracellular receptor signaling, intracellular steroid hormone receptor signaling, chromatin, nucleoplasm, receptor complex, endoplasmic reticulum membrane, and RNA polymerase II transcription Factor Activity. The KEGG/DAVID database enrichment study found that metabolic pathways, PPAR signaling pathways, cancer pathways/PPAR signaling pathways, insulin resistance, and ovarian steroidogenesis all play essential roles in the treatment of obesity and OA. The protein-protein interaction (PPI) network was used to screen nine main targets: PPARG, PPARA, MAPK3, NR3C1, PTGS2, CYP19A1, CNR1, HSD11B1, and AGTR1. Using molecular docking technology, the possible binding mechanism and degree of binding between OA and each important target were validated, demonstrating that OA has a good binding potential with each target. The molecular dynamics simulation's Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg) further demonstrated that OA has strong binding stability with each target. Additional animal studies confirmed the significance of the core target PPARG and the core pathway PPAR signaling pathway in OA anti-obesity. CONCLUSION: Overall, our study utilized a multifaceted approach to investigate the value and mechanisms of OA in treating obesity, thereby providing a novel foundation for the identification and development of natural drug treatments.
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Enfermedades Cardiovasculares , Ácido Oleanólico , Animales , Simulación del Acoplamiento Molecular , Farmacología en Red , Ácido Oleanólico/farmacología , Ácido Oleanólico/uso terapéutico , PPAR gammaRESUMEN
Uric acid (UA) is the final metabolite of purines in the liver that can cause hyperuricemia at high levels. The kidneys are the main excretory organs for UA. The excessive accumulation of UA in the kidneys causes the development of hyperuricemia that often leads to renal injury. Eupatilin (Eup) is a flavonoid natural product that possesses various pharmacological properties such as antioxidant, anti-cancer, and anti-inflammatory. We were interested in exploring the potential role of Eup in lowering UA and nephroprotective. We initially investigated the effects of Eup on xanthin oxidase (XOD) activity in vitro, followed by investigating its ability to lower UA levels, anti-inflammatory effects, nephroprotective effects, and the underlying mechanisms using hyperuricemia rats sustained at high UA level. The results showed that Eup had an inhibitory effect on XOD activity in vitro and significantly reduced serum UA, creatinine, BUN, IL-1ß and IL-6 levels in hyperuricemic rats, ameliorating inflammation, renal oxidative stress and pathological injury. Furthermore, Eup inhibited ADA and XOD enzyme activities in the liver and serum and modulated GLUT9, URAT1 and ABCG2 protein expression in the kidneys and ileum. Our findings provide a scientific basis for suggesting Eup as an option for a potential treatment for hyperuricemia.
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Hiperuricemia , Ratas , Animales , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Xantina Oxidasa , Riñón , Flavonoides/farmacología , Flavonoides/uso terapéutico , Ácido Úrico/metabolismo , Antiinflamatorios/farmacologíaRESUMEN
Hepatocellular carcinoma (HCC) is a significant global health concern as it ranks as the sixth most common malignant tumor and the third leading cause of cancer-related deaths. In this study, we analyzed the expression of centromere protein B (CENPB) mRNA in HCC using TCGA and GEO datasets. Immunohistochemistry (IHC) was performed to determine CENPB protein levels in 490 HCC patients. Our findings revealed higher expression of CENPB mRNA in HCC tissues across the three datasets. Additionally, as the pathological stage and histological grade advanced, CENPB expression increased. Patients with elevated levels of CENPB mRNA and protein demonstrated shorter overall survival (OS) and recurrence-free survival (OS). Notably, CENPB protein showed prognostic value in patients with stage I/II, AFP levels below 400 ng/ml, and tumor size less than 5 cm. Using multivariate regression analysis in 490 HCC patients, we developed nomograms to predict 1-year, 3-year, and 5-year OS and RFS. Knockdown of CENPB in Hep3B and MHCC97 cell lines resulted in significant inhibition of cell proliferation and invasion. Furthermore, bioinformatics analysis identified miR-29a as a potential negative regulator of CENPB expression, which was validated through a dual-luciferase reporter assay. In conclusion, our findings suggest that CENPB may serve as an oncogenic factor in HCC and is directly regulated by miR-29a, highlighting its potential as a promising therapeutic target.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , MicroARNs/metabolismo , Proteína B del Centrómero/genética , Proteína B del Centrómero/metabolismo , ARN Mensajero , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular TumoralRESUMEN
We demonstrated a temperature-compensated optofluidic DNA biosensor available for microfluidic chip. The optofluidic sensor was composed of an interferometer and a fiber Bragg grating (FBG) by femtosecond laser direct writing micro/nano processing technology. The sensing arm of the interferometer was suspended on the inner wall of the microchannel and could directly interact with the microfluid. With the immobilization of the single stranded probe DNA (pDNA), this optofluidic biosensor could achieve specific detection of single stranded complementary DNA (scDNA). The experimental results indicated that a linear response within 50 nM and the detection limit of 1.87 nM were achieved. In addition, the optofluidic biosensor could simultaneously monitor temperature to avoid temperature fluctuations interfering with the DNA hybridization detection process. And, the optofluidic detection channel could achieve fast sample replacement within 10 s at a flow rate of 2 µL/min and sample consumption only required nanoliters. This optofluidic DNA biosensor had the advantages of label-free, good specificity, dual parameter detection, low sample consumption, fast response, and easy repeatable preparation, which was of great significance for the field of DNA hybridization research and solving the temperature sensitivity problem of biosensors and had good prospects in biological analysis.
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Técnicas Biosensibles , Microfluídica , Temperatura , Técnicas Biosensibles/métodos , Tecnología de Fibra Óptica , ADN/genética , ADN/análisis , ADN de Cadena SimpleRESUMEN
Manipulation of micro- and nanoscale objects is an essential procedure in many detection and sensing applications, including disease diagnosis and environmental monitoring. Induced-charge electro-osmotic (ICEO) vortices present excellent advantages in the enrichment and selection of micro/nanoscale particles for downstream detection due to gentle conditions and contactless operation, but the application of this method is currently constrained by the throughput. Double-layer charging at the ends of bipolar electrodes can maintain a continuous flow of electric current in the fluidically isolated channels, which provides a feasible method to manipulate particles using parallel ICEO vortices, promoting throughput of particle manipulation without compromising efficiency and overcoming the complicated ohmic contact of electrodes. Encouraged by these, we put forward a novel method with parallel ICEO vortices to manipulate micro/nanoscale samples for downstream detection. First, we study the extension regulation of the low-frequency electric field and mediating effect of the open BPEs on the extended electric field and characterize electric equilibrium states of microparticles and their voltage dependence. Afterward, we leverage this method to enrich nanoparticles for detection of low-abundance nanoparticles with about 20- and 40-fold fluorescence intensities by integrating with a simple fiber-optic sensor. Furthermore, this technique is engineered for the selection of targeted microalgae to continuously detect their proliferation behaviors by combining with a homemade electrical impedance spectroscopy device. This method can reinforce the throughput of ICEO vortices and enables it to integrate with simple and economical sensors to accomplish disease diagnosis and environmental monitoring.
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Microalgas , Nanopartículas , Nanopartículas/química , Electrodos , Electricidad , Tecnología de Fibra ÓpticaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Fufang-Zhenzhu-Tiaozhi capsule (FTZ), a Traditional Chinese Medicine (TCM) patent prescription commonly used in clinical practice, has a significant curative effect on hyperglycemia and hyperlipidemia. Previous studies have shown that FTZ can treat diabetes, but the effect of FTZ on ß-cell regeneration needs to be further explored in T1DM mice. AIM OF THE STUDY: The aim is to investigate the role of FTZ in promoting ß-cell regeneration in T1DM mice, and to further explore its mechanism. MATERIALS AND METHODS: C57BL/6 mice were used as control. NOD/LtJ mice were divided into the Model group and FTZ group. Oral glucose tolerance, fasting blood glucose, and fasting insulin level were measured. Immunofluorescence staining was used to detect the level of ß-cell regeneration and the composition of α-cells and ß-cells in islets. Hematoxylin and eosin staining was used to detect the infiltration degree of inflammatory cells. The apoptosis of islet cells was detected by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling. Western blotting was used to detect the expression levels of Pancreas/duodenum homeobox protein 1 (PDX-1), V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA), and Neurogenin-3 (NGN3). RESULTS: FTZ could increase insulin levels and reduce the glucose level of T1DM mice and promote ß-cell regeneration. FTZ also inhibited the invasion of inflammatory cells and the islet cell apoptosis, and maintained the normal composition of islet cells, thus preserving the quantity and quality of ß-cells. Furthermore, FTZ promoting ß-cell regeneration was accompanied by increasing the expression of PDX-1, MAFA, and NGN3. CONCLUSION: FTZ can restore the insulin-secreting function of the impaired pancreatic islet, improve blood glucose level, possibly via the enhancing ß cell regeneration via upregulation of PDX-1, MAFA, and NGN3 in T1DM mice, and may be a potential therapeutic drug for T1DM.
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Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Islotes Pancreáticos , Ratones , Animales , Diabetes Mellitus Tipo 1/metabolismo , Glucemia/metabolismo , Ratones Endogámicos NOD , Ratones Endogámicos C57BL , Islotes Pancreáticos/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina , Regeneración , Proliferación CelularRESUMEN
Liver fibrosis refers to the pathophysiological process of dysplasia on the connective tissue of the liver, caused by a variety of pathogenic factors. Glaucocalyxin A (GLA) has anticoagulation, antibacterial, anti-inflammation, antioxidant and antitumour properties. However, whether GLA ameliorates liver fibrosis or not is still unclear. In this study, a liver fibrosis model was established using male C57BL/6 mice. The mice were treated with 5 and 10 mg/kg GLA via intraperitoneal injection, respectively. The ones that were treated with 5 mg/kg OCA were used as the positive control group. The levels of liver function, liver fibrosis biomarkers and liver pathological changes were then evaluated. We also explored the effects of GLA on inflammatory response and liver cell apoptosis. In addition, we investigated the gut microbiota mechanisms of GLA on liver fibrosis. The results from this study that GLA could significantly decrease the level of liver function (AST, ALT, TBA) and liver fibrosis (HA, LN, PC-III, IV-C). On the other hand, a significant decrease in inflammation levels (IL-1ß, TNF-α) were also noted. GLA also improves CCl4-induced pathological liver injuries and collagen deposition, in addition to decreasing apoptosis levels. In addition, an increase in the ratio of Bacteroidetes and Firmicutes in liver disease was also observed. GLA also improves the gut microbiota. In conclusion, GLA attenuates CCl4-induced liver fibrosis and improves the associated gut microbiota imbalance.
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Tetracloruro de Carbono , Microbioma Gastrointestinal , Ratones , Masculino , Animales , Tetracloruro de Carbono/efectos adversos , Ratones Endogámicos C57BL , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , HígadoRESUMEN
BACKGROUND Splenic artery steal syndrome (SASS) can aggravate liver damage in patients with cirrhosis. This study explored whether SASS could be an effective therapeutic target for improving hepatic artery perfusion and liver function in patients with decompensated cirrhosis. MATERIAL AND METHODS Based on inclusion and exclusion criteria, 87 patients with hepatitis B cirrhosis and portal hypertension hypersplenism admitted to our General Surgery Department for splenectomy and pericardial devascularization surgery were selected. A total of 35 cases met the diagnostic criteria of SASS and were assigned to the SASS group; the remaining 52 cases were assigned to the control group. The indicators before, during, and after surgery were compared between the 2 groups. RESULTS There were no significant differences in preoperative and intraoperative indicators between SASS group and control group (P>0.05). The MELD score 7 days after surgery and the hepatic artery diameter and hepatic artery velocity 14 days after surgery in both groups were significantly better than before surgery. The MELD score 7 days after surgery in the SASS group was significantly better than that in the control group, and the hepatic artery diameter and hepatic artery velocity 14 days after surgery in the SASS group were significantly better than those in the control group (P<0.05). CONCLUSIONS Splenectomy and pericardial devascularization surgery was an effective treatment to redirect blood flow to the hepatic artery for cirrhotic patients diagnosed with SASS. The introduction of cirrhotic SASS into clinical practice may benefit more patients with cirrhotic portal hypertension and hypersplenism.
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Hiperesplenismo , Hipertensión Portal , Arteria Esplénica , Humanos , Hipertensión Portal/complicaciones , Cirrosis Hepática/complicaciones , Estudios Retrospectivos , Arteria Esplénica/cirugía , EsplenectomíaRESUMEN
BACKGROUND: Radiotherapy is an important treatment for lung cancer, mainly by triggering DNA double-strand breaks to induce cell death. Blocking DNA damage repair can increase the radiosensitivity of tumor cells. Recent studies have identified long noncoding RNAs as key regulators in DNA damage repair. The lncRNA ANRIL was previously shown to be involved in homologous recombination (HR) repair, but its specific mechanism has not been fully elucidated. METHODS: The downstream interacting miRNAs of ANRIL were predicted according to miRanda software. Fluorescence quantitative PCR was used to detect the expression levels of ANRIL and candidate miRNAs. Clone formation experiment and cell viability assays detect cell viability after ionizing radiation. Apoptosis assay was used to detect the apoptosis of cells after 8 h of ionizing radiation. Western blot analysis and immunofluorescence assays verified the protein expression levels of the downstream target molecule PARP1 of miR-7-5p and key molecules in the HR pathway. Fluorescent reporter gene experiments were used to verify the interaction between ANRIL and miR-7-5p and between miR-7-5p and PARP1. RESULTS: Bioinformatics analysis and qPCR validation suggested that miR-7-5p might be a downstream molecule of ANRIL. The expression of miR-7-5p was up-regulated after knockdown of ANRIL, and the expression of miR-7-5p was down-regulated after overexpression of ANRIL. Meanwhile, there was a negative correlation between ANRIL and miR-7-5p expression changes before and after ionizing radiation. The luciferase reporter gene assay confirmed the existence of ANRIL binding site with miR-7-5p, and found that transfection of miR-7-5p inhibitor can reduce the radiation sensitivity of ANRIL-KD cells. A downstream target molecule of miR-7-5p related to HR repair, PARP1, was screened through website prediction. Subsequently, it was confirmed by Western blot and luciferase reporter assays that miR-7-5p could down-regulate the expression of PARP1, and there was a miR-7-5p binding site on the 3'UTR of PARP1 mRNA. This suggests that ANRIL may act as a competitive endogenous RNA to bind miR-7-5p and upregulate the expression of PARP1. Western blot and immunofluorescence staining were used to detect the expression changes of HR repair factors in ANRIL-KD cells after ionizing radiation, and it was found that knockdown of ANRIL can inhibit the expression of PARP1, BRCA1 and Rad51, hinder radiation-induced HR repair, and eventually result in resensitizing ANRIL-KD cells to ionizing radiation. CONCLUSIONS: Our findings provide evidence that ANRIL targets the miR-7-5p/PARP1 axis to exert its regulatory effect on HR repair, suggesting that altering ANRIL expression may be a promising strategy to overcome radiation resistance.
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Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Humanos , Línea Celular Tumoral , Proliferación Celular/genética , Reparación del ADN/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , MicroARNs/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Reparación del ADN por Recombinación , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Background: Excessive doses of electromagnetic radiation pose a negative impact on the central nervous system and lead to mental disorders. Molecular hydrogen can scavenge intracellular hydroxyl radicals, acting as an antioxidant, anti-apoptotic and anti-inflammatory agent. We seek to assess the capability of molecular hydrogen to ameliorate brain damage induced by electromagnetic radiation. Methods: NEMP (nuclear electromagnetic pulse), a subset of electromagnetic pulse with high voltage value that could cause severe brain injury, was applied to this study. Male wild-type rats were divided into four groups: the control group, the H2 (Molecular hydrogen) group, the NEMP group and the NEMP+H2 group. Rats in the H2 group and the NEMP+H2 group were fed with saturated hydrogen-rich water from 3 days before NEMP exposure (electromagnetic field intensity 400 kV/m, rising edge 20 ns and pulse width 200 ns) to the day of sacrifice. One day after exposure, animal behavior experiments were performed, and samples for transcriptomics and metabolomics analysis were collected. Seven days after exposure, histopathological experiments were conducted. Results: The data from the elevated plus maze and the open field test showed that NEMP exposure elicited anxiety-like behavior in rats, which could be alleviated by H2 treatment. Histopathological results manifested that NEMP exposure-induced injuries of the neurons in the hippocampus and amygdala could be attenuated by H2 treatment. Transcriptomic results revealed that NEMP exposure had a profound effect on microtubule structure in the brain. And the combined analysis of transcriptomics and metabolomics showed that H2 has a significant impact on the neuroactive ligand-receptor interaction, synaptic vesicle cycle and synapse etc. Moreover, it was indicated that the glutathione metabolic pathway played a vital role in the NEMP exposure-induced damage and the protective activity of H2. Conclusions: H2 is identified as a potent agent against NEMP exposure-induced brain damage and has the potential to be a promising electromagnetic radiation protectant.
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Lesiones Encefálicas , Transcriptoma , Ratas , Masculino , Animales , Estrés Oxidativo , Fenómenos Electromagnéticos , Hidrógeno/química , Hidrógeno/farmacología , EncéfaloRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Fufang-zhenzhu-tiaozhi formula (FTZ) is a patented preparation of traditional Chinese medicine that has been used to treat hyperglycemia and hyperlipidemia in the clinic for almost 10 years. Our previous study had demonstrated that FTZ can protect islet ß cell injury in vitro. However, the efficacy of FTZ on ß cell regeneration in vivo and the involved anti-diabetic mechanism remains unknown. AIM OF THE STUDY: We aim to investigate the effects of FTZ as a good remedy for islet protection and ß cell regeneration, and to reveal the underlying mechanism. MATERIALS AND METHODS: C57BL/6 mice were fed with high-fat diet for 3 weeks and then intraperitoneally injected with streptozotocin (90 mg/kg/d × 1 d) to establish type 2 diabetes (T2D) models. Mice in each group were divided into three batches that sacrificed after 3, 7 and 28 days of FTZ administration. Body weight, blood glucose, and oral glucose tolerance test were measured at indicated time points. Fasting insulin was determined by enzyme-linked immunosorbent assay (ELISA) kit. Neonatal ß cell was assessed by insulin & PCNA double immunofluorescence staining, and the underlying mechanisms related to ß cell regeneration were further performed by hematoxylin-eosin staining, insulin & glucagon double immunofluorescence staining and Western blot. RESULTS: FTZ and metformin can significantly help with the symptoms of DM, such as alleviating weight loss, reducing blood glucose, improving the level of insulin in vivo, and relieving insulin resistance, suggesting FTZ and metformin treatment maintained the normal morphological function of islet. Notably, ß cell regeneration, which is indicated by insulin and PCNA double-positive cells, was promoted by FTZ, whereas few neonatal ß cells were observed in metformin group. Hematoxylin-eosin staining, and its quantification results showed that FTZ effectively prevented the invasion of inflammatory cells into the islets in diabetic mice. Most ß cells in the islets of diabetic model mice were devoid, and the islets were almost all α cells, while the diabetic mice administered FTZ could still maintain about half of the ß cells in the islet. Furthermore, FTZ upregulated the expression of critical transcription factors during ß cell development and maturation (such as PDX-1, MAFA and NGN3) in diabetic mice. CONCLUSIONS: FTZ can alleviate diabetes symptoms and promote ß cell regeneration in diabetic mice. Moreover, FTZ promotes ß cell regeneration by preserving islet (resisting inflammatory cells invading islets), maintaining the number of ß cells in islets, and increasing the expression of PDX-1, MAFA and NGN3.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Islotes Pancreáticos , Metformina , Ratones , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Eosina Amarillenta-(YS)/metabolismo , Eosina Amarillenta-(YS)/farmacología , Hematoxilina/metabolismo , Hematoxilina/farmacología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratones Endogámicos C57BL , Insulina , Regeneración , Metformina/farmacologíaRESUMEN
Since most of the existing models based on the microgrids (MGs) are nonlinear, which could cause the controller oscillate, resulting in the excessive line loss, and the nonlinear could also lead to the controller design difficulty of MGs system. Therefore, this article researches the distributed voltage recovery consensus optimal control problem for the nonlinear MGs system with N -distributed generations (DGs), in the case of providing stringent real power sharing. First, based on the distributed cooperative control concept of multiagent systems and the critic neural networks (NNs), a novel distributed secondary voltage recovery consensus optimal control protocol is constructed via applying the backstepping technique and nonzero-sum (NZS) differential game strategy to realize the voltage recovery of island MGs. Meanwhile, the model identifier is established to reconstruct the unknown NZS games systems based on a three-layer NN. Then, a critic NN weight adaptive adjustment tuning law is proposed to ensure the convergence of the cost functions and the stability of the closed-loop system. Furthermore, according to Lyapunov stability theory, it is proven that all signals are uniform ultimate boundedness in the closed loop system and the voltage recovery synchronization error converges to an arbitrarily small neighborhood of the origin near. Finally, some simulation results in MATLAB illustrate the validity of the proposed control strategy.
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In traditional leak location methods, the position of the leak point is located through the time difference of pressure change points of both ends of the pipeline. The inaccurate estimation of pressure change points leads to the wrong leak location result. To address it, adaptive dynamic programming is proposed to solve the pipeline leak location problem in this article. First, a pipeline model is proposed to describe the pressure change along pipeline, which is utilized to reflect the iterative situation of the logarithmic form of pressure change. Then, under the Bellman optimality principle, a value iteration (VI) scheme is proposed to provide the optimal sequence of the nominal parameter and obtain the pipeline leak point. Furthermore, neural networks are built as the VI scheme structure to ensure the iterative performance of the proposed method. By transforming into the dynamic optimization problem, the proposed method adopts the estimation of the logarithmic form of pressure changes of both ends of the pipeline to locate the leak point, which avoids the wrong results caused by unclear pressure change points. Thus, it could be applied for real-time leak location of long-distance pipeline. Finally, the experiment cases are given to illustrate the effectiveness of the proposed method.
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ETHNOPHARMACOLOGICAL RELEVANCE: Excessive serum uric acid (SUA) causes hyperuricemic nephropathy (HN), characterized by inflammatory infiltration and tubulointerstitial fibrosis. Most recently, we demonstrated that Fufang Zhenzhu Tiaozhi (FTZ) capsule attenuated diabetic nephropathy through inhibition of renal inflammation and fibrosis. However, whether FTZ ameliorates HN is still unclear. AIM OF THE STUDY: To determine the protective roles and mechanism of FTZ in mouse renal injury and fibrosis under hyperuricemic condition. MATERIALS AND METHODS: HN mice, induced by potassium oxonate and hypoxanthine, were administrated with 600 and 1200 mg/kg FTZ (intragastrically) daily for three weeks. SUA levels, renal functions and histological changes were analyzed. Western blotting, quantitative real-time PCR (q-PCR) and RNA sequencing were used to identify the roles and underlying mechanism of FTZ in HN mice. RESULTS: We demonstrated that FTZ treatment mitigated renal injury in mice, as evidenced by the decrease in SUA, serum creatinine (SCr) and cystatin C (Cys C) levels, as well as improved renal histology. FTZ markedly attenuates inflammasome activation, collagen deposition and the imbalance of uric acid transporters. RNA-sequencing revealed a key mechanism involved in the protective effects on HN mice was related to PI3K/AKT/NF-κB pathway. Western blot also confirmed that FTZ diminished the phosphorylation of AKT and p65 in HN mice. CONCLUSIONS: FTZ prevents renal injury, inflammation and fibrosis in HN mice via promoting uric acid excretion and inhibiting PI3K/AKT/NF-κB signaling pathway.
Asunto(s)
Hiperuricemia , Ácido Úrico , Animales , Fibrosis , Inflamación/tratamiento farmacológico , Riñón , Ratones , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
CANDOR compared the safety/efficacy of carfilzomib with dexamethasone and daratumumab (KdD) to carfilzomib with dexamethasone (Kd) in adults with relapsed/refractory multiple myeloma (RRMM). This CANDOR subgroup analysis evaluated outcomes based on cytogenetic risk. Overall response rates (KdD vs. Kd) were 81% versus 56% in high-risk and 87% versus 79% in standard-risk groups. Median progression-free survival was 11.2 versus 7.4 months in high-risk (hazard ratio, 0.56 [95% CI, 0.34, 0.93]) and not reached versus 16.6 months in standard-risk groups (0.56 [95% CI, 0.39, 0.80]). These data support the efficacy of KdD in RRMM treatment, including in patients with high-risk cytogenetics.
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Protocolos de Quimioterapia Combinada Antineoplásica , Mieloma Múltiple , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Análisis Citogenético , Dexametasona/uso terapéutico , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Pronóstico , Resultado del TratamientoRESUMEN
Endoplasmic reticulum stress (ER stress) is a double-edged sword in the occurrence and development of malignant cancer. The aim of this study was to explore the roles of ER stress in metastasis and epithelial-mesenchymal transitionin triple-negative breast cancer (TNBC) and potential mechanisms. In this study, 4-PBA was administrated to inhibit the ER stress. Cell viability was evaluated using a cell counting kit-8 assay. Cell migration and invasion were identified by wound healing and transwell assay, respectively. Levels of MMP2 and MMP9 were measured by enzyme-linked immunosorbent assay and immunohistochemical staining. Western blot assay was used to assess the levels of ER stress-related proteins, Syndecan-1 (SDC-1)/Syntenin-1 (SDCBP-1)/SRY-related HMG-box 4 (SOX4) signaling and Wnt/ß-catenin signaling. Moreover, a xenograft mice model was conducted to confirm the role of ER stress in TNBC. The data indicate that the ability of viability and metastasis of breast cancer cells were stronger than normal mammary epithelial cells. More aggressiveness was manifested in TNBC cells than that in non-TNBC cells. 4-PBA significantly suppressed the viability, migration, and invasion in BC cells and inhibited the SDC/SDCBP/SOX4 axis and Wnt/ß-catenin signaling. Furthermore, heat shock protein A4 (HSPA4) overexpression stimulated ER stress and activated the SDC-1/SDCBP-1/SOX4 pathway and Wnt/ß-catenin signaling. Animal experiments showed similar results that 4-PBA repressed tumor growth and inactivated the two pathways, while HSPA4 overexpression reversed the effects of 4-PBA. In summary, inhibition of ER stress inhibited TNBC viability, migration, and invasion by Syntenin/SOX4/Wnt/ß-catenin pathway via regulation of HSPA4 in vivo and in vitro.