Management considerations and treatment outcomes for newly diagnosed prostate cancer in advanced age patients (≥80 years): real-world data from a single urological center over a 10-year period.

Background: There is ongoing debate regarding prostate cancer (PCa) screening in advanced age males, leading to treatment decisions often based on tumor staging and life expectancy. A critical gap in clinical evidence and tailored guidelines for the advanced age with PCa persists. This study aims to compare survival outcomes of various treatment approaches in this demographic. Methods: We analyzed data from a large urological center for advanced age patients suspected of having PCa between 2012 and 2022. We collected clinical and pathological characteristics and evaluated treatment modalities, including palliative therapy and definitive therapy. Propensity score matching (PSM) analysis was implemented to reduce bias between treatment modalities. Kaplan-Meier and multivariate Cox proportional hazard regression analyses were conducted to evaluate progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Results: Out of 4,333 suspected patients, 376 individuals aged 80 years and older underwent prostate biopsy. The overall detection rate of PCa was 78.7%, with a high prevalence of high-grade tumors [International Society of Urological Pathology (ISUP) grade ≥2]. Most patients (86.5%) received palliative therapy, while 13.5% underwent definitive therapy. Patients in the definitive therapy group had lower prostate-specific antigen (PSA) values, lower tumor stage, and Charlson Comorbidity Index (CCI), longer life expectancy, and a higher Geriatric 8 (G8) score compared to the palliative therapy group. The median OS for the entire cohort was 72.0 months, with 70.0 months for palliative therapy and 96.0 months for definitive therapy. Multivariable analyses identified lymphatic and bone metastasis, as well as definitive therapy, as independent prognostic factors for PFS, CSS, and OS. Conclusions: Advanced age patients, although a small group, have distinct characteristics, including higher PSA levels, positive biopsy rates, and pathological grading and staging. In medically fit elderly patients, especially those with localized PCa and a life expectancy of ≥5 years, definitive therapy could improve survival outcomes.

Research Progress of Biosensor Based on Organic Photoelectrochemical Transistor.

In order to solve the food safety problem better, it is very important to develop a rapid and sensitive technology for detecting food contamination residues. Organic photoelectrochemical transistor (OPECT) biosensor rely on the photovoltage generated by a semiconductor upon excitation by light to regulate the conductivity of the polymer channels and realize biosensor analysis under zero gate bias. This technology integrates the excellent characteristics of photoelectrochemical (PEC) bioanalysis and the high sensitivity and inherent amplification ability of organic electrochemical transistor (OECT). Based on this, OPECT biosensor detection has been proven to be superior to traditional biosensor detection methods. In this review, we summarize the research status of OPECT biosensor in disease markers and food residue analysis, the basic principle, classification, and biosensing mechanism of OPECT biosensor analysis are briefly introduced, and the recent applications of biosensor analysis are discussed according to the signal strategy. We mainly introduced the OPECT biosensor analysis methods applied in different fields, including the detection of disease markers and food hazard residues such as prostate-specific antigen, heart-type fatty acid binding protein, T-2 toxin detection in milk samples, fat mass and objectivity related protein, ciprofloxacin in milk. The OPECT biosensor provides considerable development potential for the construction of safety analysis and detection platforms in many fields, such as agriculture and food, and hopes to provide some reference for the future development of biosensing analysis methods with higher selectivity, faster analysis speed and higher sensitivity.

Intranasal Administration of Umbilical Cord Mesenchymal Stem Cell Exosomes Alleviates Parkinson's Disease.

Parkinson's disease (PD) is a common and complex neurodegenerative disease. This disease is typically characterized by the formation of Lewy bodies in multiple brain regions and dopaminergic neuronal loss in the substantia nigra pars compacta, resulting in non-motor symptoms (e.g., olfactory deficits) and motor dysfunction in the late stages. There is yet no effective cure for Parkinson's disease. Considering the neuroprotective effects of exosomes, we investigated whether intranasal administration of umbilical cord mesenchymal stem cell exosomes could improve behavioral functions in PD mice. First, exosomes were endocytosed by the cells in vitro and in vivo, indicating that exosomes can cross the blood-brain barrier. Second, we found that both motor and non-motor functions of the PD models were effectively improved during intranasal exosomes treatment. Finally, the activity of olfactory bulb neurons was improved and the loss of dopaminergic neurons in the substantia nigra pars compacta was reversed. Moreover, exosomes attenuated microglia and astrocyte activation, leading to a low level of inflammation in the brain. In conclusion, our study provided a new reference for the clinical application of exosomes in the treatment of PD.

Targeting tumor suppressor p53 for organ fibrosis therapy.

Fibrosis is a reparative and progressive process characterized by abnormal extracellular matrix deposition, contributing to organ dysfunction in chronic diseases. The tumor suppressor p53 (p53), known for its regulatory roles in cell proliferation, apoptosis, aging, and metabolism across diverse tissues, appears to play a pivotal role in aggravating biological processes such as epithelial-mesenchymal transition (EMT), cell apoptosis, and cell senescence. These processes are closely intertwined with the pathogenesis of fibrotic disease. In this review, we briefly introduce the background and specific mechanism of p53, investigate the pathogenesis of fibrosis, and further discuss p53's relationship and role in fibrosis affecting the kidney, liver, lung, and heart. In summary, targeting p53 represents a promising and innovative therapeutic approach for the prevention and treatment of organ fibrosis.

Association of clonal haematopoiesis with severe postoperative complications in patients undergoing radical oesophagectomy.

BACKGROUND: Clonal haematopoiesis (CH) is an age-associated clonal expansion of blood cells driven by leukaemia-associated somatic mutations. Although CH has been reported to be a risk factor for leukaemia and a number of non-haematopoietic diseases, its role in perioperative medicine remains unexplored. METHODS: This was a single-centre, prospective, observational study. Patients undergoing radical oesophagectomy were enrolled, and peripheral blood samples were collected for DNA sequencing. Patients with haematopoietic somatic mutations (variant allele frequencies ≥1%) in the DNMT3A gene, TET2 gene, or both were defined as CH carriers. The primary outcome was the incidence of severe postoperative complications (Clavien-Dindo classification ≥3). The secondary outcomes included the major types of postoperative complications, mortality, and other common perioperative variables. RESULTS: Clonal haematopoiesis was found in 21.2% (33/156) of the patients (mean age: 66 yr [range: 26-79 yr]; 83% males). Some 14/33 (42.4%) patients with CH had severe postoperative complications, compared with patients without CH carriers (28/123 [22.8%]; P=0.024). Multivariable logistic regression analysis showed that CH was associated with an increased risk of developing severe postoperative complications (odds ratio, 3.63; 95% confidence interval, 1.37-9.66; P=0.010). Among the major postoperative complications, the incidence of pulmonary complications was significantly higher in the patients with CH than in those without CH (15 in 33 [45.5%] vs 30 in 123 [24.4%], P=0.018). CONCLUSIONS: Clonal haematopoiesis was associated with a higher incidence of severe postoperative complications in patients undergoing radical oesophagectomy, suggesting that clonal haematopoiesis can play an important role in perioperative medicine. CLINICAL TRIAL REGISTRATION: ChiCTR2100044175 (Chinese Clinical Trial Registry, http://www.chictr.org.cn/showproj.aspx?proj=123193).

Genome-Wide Identification and Comprehensive Analysis of the FtsH Gene Family in Soybean (Glycine max).

The filamentation temperature-sensitive H (FtsH) gene family is critical in regulating plant chloroplast development and photosynthesis. It plays a vital role in plant growth, development, and stress response. Although FtsH genes have been identified in a wide range of plants, there is no detailed study of the FtsH gene family in soybean (Glycine max). Here, we identified 34 GmFtsH genes, which could be categorized into eight groups, and GmFtsH genes in the same group had similar structures and conserved protein motifs. We also performed intraspecific and interspecific collinearity analysis and found that the GmFtsH family has large-scale gene duplication and is more closely related to Arabidopsis thaliana. Cis-acting elements analysis in the promoter region of the GmFtsH genes revealed that most genes contain developmental and stress response elements. Expression patterns based on transcriptome data and real-time reverse transcription quantitative PCR (qRT-PCR) showed that most of the GmFtsH genes were expressed at the highest levels in leaves. Then, GO enrichment analysis indicated that GmFtsH genes might function as a protein hydrolase. In addition, the GmFtsH13 protein was confirmed to be localized in chloroplasts by a transient expression experiment in tobacco. Taken together, the results of this study lay the foundation for the functional determination of GmFtsH genes and help researchers further understand the regulatory network in soybean leaf development.

Switchable In Situ SO2 Capture and CF3 Migration of Enol Triflates with Peroxyl Compounds under Iron Catalysis.

Switchable in situ SO2 capture and CF3 migration of enol triflates with peroxyl compounds under iron catalysis are presented. By regulating the structure of peroxides, a variety of keto-functionalized dialkyl sulfones and α-trifluoromethyl ketones were selectively synthesized in good yields under mild conditions.

Cell membrane-based biomimetic nanosystems for advanced drug delivery in cancer therapy: A comprehensive review.

Natural types of cells display distinct characteristics with homotypic targeting and extended circulation in the blood, which are worthy of being explored as promising drug delivery systems (DDSs) for cancer therapy. To enhance their delivery efficiency, these cells can be combined with therapeutic agents and artificial nanocarriers to construct the next generation of DDSs in the form of biomimetic nanomedicines. In this review, we present the recent advances in cell membrane-based DDSs (CDDSs) and their applications for efficient cancer therapy. Different sources of cell membranes are discussed, mainly including red blood cells (RBC), leukocytes, cancer cells, stem cells and hybrid cells. Moreover, the extraction methods used for obtaining such cells and the mechanism contributing to the functional action of these biomimetic CDDSs are explained. Finally, a future perspective is proposed to highlight the limitations of CDDSs and the possible resolutions toward clinical transformation of currently developed biomimetic chemotherapies.

Renal denervation ameliorates cardiac metabolic remodeling in diabetic cardiomyopathy rats by suppressing renal SGLT2 expression.

This study aimed to investigate the effects of renal denervation (RDN) on diabetic cardiomyopathy (DCM) and explore the related mechanisms. Male Sprague-Dawley rats were fed high-fat chow and injected with low-dose streptozotocin to establish a DCM model. Six rats served as controls. The surviving rats were divided into three groups: control group, DCM group and DCM + RDN group. RDN surgery was performed in the fifth week. At the end of the experiment, all rats were subjected to 18F-FDG PET/CT and metabolic cage studies. Cardiac function and structure were evaluated by echocardiography and histology. Myocardial substrate metabolism and mitochondrial function were assessed by multiple methods. In the 13th week, the DCM rats exhibited cardiac hypertrophy and interstitial fibrosis accompanied by diastolic dysfunction. RDN ameliorated DCM-induced cardiac dysfunction (E/A ratio: RDN 1.07 ± 0.18 vs. DCM 0.93 ± 0.12, P < 0.05; E/E' ratio: RDN 10.74 ± 2.48 vs. DCM 13.25 ± 1.99, P < 0.05) and pathological remodeling (collagen volume fraction: RDN 5.05 ± 2.05% vs. DCM 10.62 ± 2.68%, P < 0.05). Abnormal myocardial metabolism in DCM rats was characterized by suppressed glucose metabolism and elevated lipid metabolism. RDN increased myocardial glucose uptake and oxidation while reducing the absorption and utilization of fatty acids. Meanwhile, DCM decreased mitochondrial ATP content, depolarized the membrane potential and inhibited the activity of respiratory chain complexes, but RDN attenuated this mitochondrial damage (ATP: RDN 30.98 ± 7.33 µmol/gprot vs. DCM 22.89 ± 5.90 µmol/gprot, P < 0.05; complexes I, III and IV activity: RDN vs. DCM, P < 0.05). Furthermore, both SGLT2 inhibitor and the combination treatment produced similar effects as RDN alone. Thus, RDN prevented DCM-induced cardiac dysfunction and pathological remodeling, which is related to the improvement of metabolic disorders and mitochondrial dysfunction.

Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload.

Objectives: Sestrin2 (Sesn2) has been demonstrated to be a cysteine sulfinyl reductase and protects cells from multiple stress insults, including hypoxia, endoplasmic reticulum stress, and oxidative stress. However, the roles and mechanisms of Sesn2 in pressure overload-induced mouse cardiac hypertrophy have not been clearly clarified. This study intended to investigate whether sestrin2 (Sesn2) overexpression could prevent pressure overload-induced cardiac hypertrophy via an AMPKα2 dependent pathway through conditional knockout of AMPKα2. Methods and results: Sesn2 expression was significantly increased in mice hearts at 2 and 4 weeks after aortic banding (AB) surgery, but decreased to 60-70% of the baseline at 8 weeks. Sesn2 overexpression (at 3, 6, and 9 folds) showed little cardiac genetic toxicity in transgenic mice. Cardiac dysfunctions induced by pressure overload were attenuated by cardiomyocyte-specific Sesn2 overexpression when measured by echocardiography and hemodynamic analysis. Results of HE and PSR staining showed that Sesn2 overexpression significantly alleviated cardiac hypertrophy and fibrosis in mice hearts induced by pressure overload. Meanwhile, adenovirus-mediated-Sesn2 overexpression markedly suppressed angiotensin II-induced neonatal rat cardiomyocyte hypertrophy in vitro. Mechanistically, Sesn2 overexpression increased AMPKα2 phosphorylation but inhibited mTORC1 phosphorylation. The cardiac protections of Sesn2 overexpression were also via regulating oxidative stress by enhancing Nrf2/HO-1 signaling, restoring SOD activity, and suppressing NADPH activity. Particularly, we first proved the vital role of AMPKα2 in the regulation of Sesn2 with AMPKα2 knockout (AMPKα2-/-) mice and Sesn2 transgenic mice crossed with AMPKα2-/-, since Sesn2 overexpression failed to improve cardiac function, inhibit cardiac hypertrophy and fibrosis, and attenuate oxidative stress after AMPKα2 knockout. Conclusion: This study uniquely revealed that Sesn2 overexpression showed little genetic toxicity in mice hearts and inhibited mTORC1 activation and oxidative stress to protect against pressure overload-induced cardiac hypertrophy in an AMPKα2 dependent pathway. Thus, interventions through promoting Sesn2 expression might be a potential strategy for treating pathological cardiac hypertrophy and heart failure.

Cardiomyocyte-Specific RIP2 Overexpression Exacerbated Pathologic Remodeling and Contributed to Spontaneous Cardiac Hypertrophy.

This study aimed to investigate the role and mechanisms of Receptor interacting protein kinase 2 (RIP2) in pressure overload-induced cardiac remodeling. Human failing or healthy donor hearts were collected for detecting RIP2 expression. RIP2 cardiomyocyte-specific overexpression, RIP2 global knockout, or wild-type mice were subjected to sham or aortic banding (AB) surgery to establish pressure overload-induced cardiac remodeling in vivo. Phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) were used for further investigation in vitro. The expression of RIP2 was significantly upregulated in failing human heart, mouse remodeling heart, and Ang II-treated NRCMs. RIP2 overexpression obviously aggravated pressure overload-induced cardiac remodeling. Mechanistically, RIP2 overexpression significantly increased the phosphorylation of TAK1, P38, and JNK1/2 and enhanced IκBα/p65 signaling pathway. Inhibiting TAK1 activity by specific inhibitor completely prevented cardiac remodeling induced by RIP2 overexpression. This study further confirmed that RIP2 overexpression in NRCM could exacerbate PE-induced NRCM hypertrophy and TAK1 silence by specific siRNA could completely rescue RIP2 overexpression-mediated cardiomyocyte hypertrophy. Moreover, this study showed that RIP2 could bind to TAK1 in HEK293 cells, and PE could promote their interaction in NRCM. Surprisingly, we found that RIP2 overexpression caused spontaneous cardiac remodeling at the age of 12 and 18 months, which confirmed the powerful deterioration of RIP2 overexpression. Finally, we indicated that RIP2 global knockout attenuated pressure overload-induced cardiac remodeling via reducing TAK1/JNK1/2/P38 and IκBα/p65 signaling pathways. Taken together, RIP2-mediated activation of TAK1/P38/JNK1/2 and IκBα/p65 signaling pathways played a pivotal role in pressure overload-induced cardiac remodeling and spontaneous cardiac remodeling induced by RIP2 overexpression, and RIP2 inhibition might be a potential strategy for preventing cardiac remodeling.

ROS-mediated liposomal dexamethasone: a new FA-targeted nanoformulation to combat rheumatoid arthritis via inhibiting iRhom2/TNF-α/BAFF pathways.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder that has seriously affected human health worldwide and its current management requires more successful therapeutic approaches. The combination of nanomedicines and pathophysiology into one system may provide an alternative strategy for precise RA treatment. In this work, a practical ROS-mediated liposome, abbreviated as Dex@FA-ROS-Lips that comprised synthetic dimeric thioether lipids (di-S-PC) and a surface functionalized with folic acid (FA), was proposed for dexamethasone (Dex) delivery. Incorporation with thioether lipids and a FA segment significantly improved the triggered release and improved the triggered release of cytotoxic Dex as well as the active targeting of RA, altering its overall pharmacokinetics and safety profiles in vivo. As proof, the designed Dex@FA-ROS-Lips demonstrated effective internalization by LPS-activated Raw264.7 macrophages with FA receptor overexpression and released Dex at the inflammatory site due to the ROS-triggered disassembly. Intravenous injection of this Dex@FA-ROS-Lips into adjuvant-induced arthritis (AIA) mice led to its incremental accumulation in inflamed joint tissues and significantly alleviated the cartilage destruction and joint swelling via suppression of proinflammatory cytokines (iRhom2, TNF-α and BAFF), as compared to the effect of commercial free Dex. Importantly, the Dex@FA-ROS-Lips nanoformulation showed better hemocompatibility with less adverse effects on the body weight and immune organ index of AIA mice. The anti-inflammatory mechanism of Dex@FA-ROS-Lips was further studied and it was found that it is possibly associated with the down-regulation of iRhom2 and the activation of the TNF-α/BAFF signaling pathway. Therefore, the integration of nanomedicines and the RA microenvironment using multifunctional Dex@FA-ROS-Lips shall be a novel RA treatment modality with full clinical potential, and based on the enhanced therapeutic effect, the signaling pathway of iRhom2/TNF-α/BAFF reasonably explained the mechanism of Dex@FA-ROS-Lips in anti-RA, which suggested a molecular target for RA therapy and other inflammatory diseases.

Discovery of 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents via repressing PI3K/AKT/Smad and JAK2/STAT3 pathways.

Liver fibrosis is one of the most common pathological consequences of chronic liver diseases (CLD). To develop effective antifibrotic strategies, a novel class of 1-(substituted phenyl)-1,8-naphthalidine-3-carboxamide derivatives were designed and synthesized. By means of the collagen type I α 1 (COL1A1)-based screening and cytotoxicity assay in human hepatic stellate cell (HSC) line LX-2, seven compounds were screened out from total 60 derivatives with high inhibitory effect and relatively low cytotoxicity for further COL1A1 mRNA expression analysis. It was found that compound 17f and 19g dose-dependently inhibited the expression of fibrogenic markers, including α-smooth muscle actin (α-SMA), matrix metalloprotein 2 (MMP-2), connective tissue growth factor (CTGF) and transforming growth factor ß1 (TGFß1) on both mRNA and protein levels. Further mechanism studies indicated that they might suppress the hepatic fibrogenesis via inhibiting both PI3K/AKT/Smad and non-Smad JAK2/STAT3 signaling pathways. Furthermore, 19g administration attenuated hepatic histopathological injury and collagen accumulation, and reduced fibrogenesis-associated protein expression in liver tissues of bile duct ligation (BDL) rats, showing significant antifibrotic effect in vivo. These findings identified 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents, and provided valuable information for further structure optimization.

The 4-hook anchor coaxial needle with scaled suture is superior to the double spring coil for preoperative localization.

BACKGROUND: Preoperative localization of small size pulmonary nodules is challenging, but it is necessary for surgical resection of early lung cancer. As a new device for preoperative localization, the 4-hook-anchor coaxial needle with scaled suture was tentatively applied in our department to improve the effect of preoperative localization. However, double spring coil, as a proven positioning technology, used to be our preferred method in the past. We did a retrospective single-centre research driven by the interest on which one should be the first choice for preoperative localization among these two approaches. METHODS: We performed a retrospective analysis on 100 patients undergoing surgery with the new coaxial needle from 2019 to 2020, and 98 patients undergoing double spring coil from 2017 to 2019. The duration of localization, success rate, operation time, intraoperative bleeding, and positioning-related complications of these two groups of patients were examined in this study. RESULTS: There were no significant differences between the two groups of patients in terms of the success rate. However, the new coaxial needle seemed to be able to shorten the duration of preparative localization and operation time by accelerating the efficiency of exploring small nodules intraoperatively, and also decreased the risk of positioning-related pneumothorax and pulmonary hemorrhage. The logistic analysis indicated that the puncture depth was an independent risk factor for overall complications. Meanwhile, previous lung diseases and positioning time were independent risk factors for pneumothorax, besides pneumorrhagia and depth of penetration as well. CONCLUSIONS: The new coaxial needle can save time for both radiologists and thoracic surgeons, while reducing the risk of positioning-related complications. We support its application clinically instead of the double spring coil.

Apocynin attenuates diabetic cardiomyopathy by suppressing ASK1-p38/JNK signaling.

Diabetic cardiomyopathy (DCM) significantly increased the morbidity of heart failure in diabetic patients. Long-time oxidative stress is an indisputable contributor for DCM development. Apocynin (APO) has been suggested to be a potential drug against oxidative stress. The study aims to find out the effects of APO on DCM and the related mechanisms. Mice were randomly divided into four groups: control (CON), APO, DCM and DCM + APO. Echocardiography analyses, histological analyses, Western blot and RT-PCR were used to explore the roles and mechanisms of APO in DCM. Isolated neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (CFs) were used for further confirming the APO treatment effects in vitro. Deteriorated cardiac function, enlarged cardiomyocytes, excess cardiac fibrosis and significant cardiac oxidative stress were observed in DCM group. However, APO treatment successfully improved cardiac function, decreased cardiac hypertrophy and fibrosis, and depressed oxidative stress. Mechanistically, APO treatment markedly suppressed apoptosis signal regulating kinase 1(ASK1)-p38/c-jun N-terminal kinase (JNK) signaling and reduced apoptosis. It also inhibited NRCM apoptosis and CF activation via depressing ASK1-p38/JNK signaling in vitro. Moreover, adenovirus-mediated ASK1 overexpression completely removed the protection of APO in vitro. In conclusion, APO treatment could effectively attenuate DCM-associated injuries in vivo and protect against high glucose-induced NRCM and CF injuries in vitro via suppressing ASK1-p38/JNK signaling. APO might be a potential ASK1 inhibitor for treating DCM.

[Effect of NF-κB Inhibitor PDTC on Proliferation and Apoptosis of Acute Leukemia Cell HL-60].

OBJECTIVE: To explore the effect of nuclear factor kappa-B (NF-κB) inhibitor pyrrolidine dithiocarbamate (PDTC) on the proliferation and apoptosis of acute leukemia cell HL-60. METHODS: HL-60 cells were cultured with PDTC of 0, 25, 50, 100 µmol/L for 24, 48, 72 h. The inhibition rate of cell proliferation was detected by CCK-8 assay. Cell apoptosis was detected by Hoechst staining. Cell cycle was detected by flow cytometry. The expression of B-cell lymphoma-2 (BCL-2), BCL-2 associated X protein (BAX), cyclinD1, activated cysteinyl aspartate specific proteinase (cleaved caspase 3), cleaved caspase 8 and activation of NF-κB signal pathway related protein was detected by Western blot. RESULTS: After the HL-60 cells were cultured with PDTC of 25, 50, 100 µmol/L for 24, 48, 72 h, the inhibition rate of cell proliferation increased with the enhancement of PDTC concentration at the same time point (r=0.924, P<0.01). At the same PDTC concentration, the inhibition rate of cell proliferation increased with prolonging of time (r=0.952, P<0.01). After HL-60 cell was cultured with PDTC of 25, 50, 100 µmol/L for 48 h, compared with control group, PDTC of 25, 50, 100 µmol/L increased the cell apoptotic rate, arrested cell cycle at G1 phase (P<0.01), the expression of BCL-2, cyclinD1 and p-NF-κB p65 was down-regulated(P<0.05), the expression of BAX, cleaved caspase 3, cleaved caspase 8 was up-regulated(P<0.01). PDTC of 50, 100 µmol/L down-regulated the expression of p-inhibitor of NF-κB (p-IκBα)(P<0.01). CONCLUSION: PDTC can inhibit acute leukemia HL-60 cell proliferation and induce cell apoptosis.

Resveratrol Inhibits Ischemia-Induced Myocardial Senescence Signals and NLRP3 Inflammasome Activation.

AIMS: The aim of this study was to investigate whether resveratrol (RSV) could ameliorate ischemia- and hypoxia-associated cardiomyocyte apoptosis and injury via inhibiting senescence signaling and inflammasome activation. MATERIALS AND METHODS: Mice were treated with RSV by gastric tube (320 mg/kg/day) or vehicle one week before left coronary artery ligation or sham surgery until the end of the experiments. After pressure-volume loop analysis, mouse hearts were harvested for histopathological (including PSR, TTC, TUNEL staining, immunohistochemistry, and immunofluorescence) and molecular analysis by western blotting and RT-PCR. In addition, neonatal rat cardiomyocytes (NRCMs), cardiac fibroblasts (CFs), and macrophages were isolated for in vitro experiments. Key Findings. RSV treatment decreased mortality and improved cardiac hemodynamics. RSV inhibited the expression of senescence markers (p53, p16, and p19), inflammasome markers (NLRP3 and Cas1 p20), and nuclear translocation of NF-κB, hence alleviating infarction area, fibrosis, and cell apoptosis. RSV also inhibited expression of interleukin- (IL-) 1ß, IL-6, tumor necrosis factor-α, and IL-18 in vivo. In in vitro experiment, RSV prevented hypoxia-induced NRCM senescence and apoptosis. After inhibition of sirtuin 1 (Sirt1) by EX27, RSV failed to inhibit p53 acetylation and expression. Moreover, RSV could inhibit expression of NLRP3 and caspase 1 p20 in NRCMs, CFs, and macrophages, respectively, in in vitro experiments. Significance. Our findings revealed that RSV protected against ischemia-induced mouse heart injury in vivo and hypoxia-induced NRCM injury in vitro via regulating Sirt1/p53-mediated cell senescence and inhibiting NLRP3-mediated inflammasome activation.

Combination treatment of perifosine and valsartan showed more efficiency in protecting against pressure overload induced mouse heart failure.

The optimum strategy for heart failure (HF) treatment has yet to be elucidated. This study intended to test the benefit of a combination of valsartan (VAL) and perifosine (PER), a specific AKT inhibitor, in protecting against pressure overload induced mouse HF. Mouse were subjected to aortic banding (AB) surgery to establish HF models and then were given vehicle (HF), VAL (50 mg/kg/d), PER (30 mg/kg/d) or combination of VAL and PER for 4 weeks. Mouse with sham surgery treated with VEH were used for control (VEH). VAL or PER treatment could significantly alleviate mouse heart weight, attenuate cardiac fibrosis and improve cardiac function. The combination treatment of VAL and PER presented much better benefit compared with VAL or PER group respectively. PER treatment significantly inhibited AKT/GSK3ß/mTORC1 signaling. Besides the classic AT1 inhibition, VAL treatment significantly inhibited MAPK (ERK1/2) signaling. Furthermore, VAL and PER treatment could markedly prevent neonatal rat cardiomyocyte hypertrophy and the activation of neonatal rat cardiac fibroblast. Combination of VAL and PER also presented superior beneficial effects than single treatment of VAL or PER in vitro experiments respectively. This study presented that the combination of valsartan and PER may be a potential treatment for HF prevention.

Levels and human health risk assessments of heavy metals in fish tissue obtained from the agricultural heritage rice-fish-farming system in China.

China began to practice Rice-fish-farming system (RFFS) 1700 years ago. Nowadays, the widely spread of metals could be potential threats to the quality of RFFS fish. In this study, Pb, Cd, Hg, As and Cr as the top five most toxic heavy metals were determined in six species of RFFS fish meat obtained from 7 provinces in south China. The mean concentrations of metals in RFFS fish followed Pb (36.89 µg/kg) > As (33.36 µg/kg) > Cr (18.54 µg/kg) > Hg (16.35 µg/kg) > Cd (2.01 µg/kg), which were mostly lower in comparison with fish from traditional aquaculture systems raised by fish feeds. Grass carp obtained lower metal concentrations compared with other fishes, possibly indicating the importance of feeding habits of RFFS fish. Concentrations of metals in fish and RFFS sediment were in good correlations, and benthic fish obtained high pollution levels, suggesting the accumulation of metals through the direct contact with sediment. Risks assessments coupled with Monte Carlo simulation indicated the potential non-carcinogenic risks and carcinogenic risks decreased following As > Hg > Cr ≈ Pb > Cd, and As > Cr > Cd > Pb, respectively. These results suggested RFFS is still a successful mode of green agriculture.

Design and synthesis of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides as novel dual inhibitors of respiratory syncytial virus and influenza virus A.

Respiratory syncytial virus (RSV) and influenza A virus (IAV) are two of the most common viruses that cause substantial morbidity and mortality in infants, young children, elderly persons, and immunocompromised individuals worldwide. Currently, there are no licensed vaccines or selective antiviral drugs against RSV infections and most IAV strains become resistant to clinical anti-influenza drug. Here, we described the discovery of a series of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamide as novel and potent RSV and IAV dual inhibitors. Thirty-five derivatives were designed, prepared, and evaluated for their anti-RSV and anti-IAV activities. Among the tested compounds, 14'c, 14'e, 14'f, 14'h, and 14'i exhibited excellent activity against both RSV and IAV, which showed low micromolar to sub-micromolar EC50 values. Further, compounds 14'c and 14'e were identified as the most promising dual inhibitors with lesser cytotoxicity than the clinical drug, ribavirin. These findings may contribute to the development of a lead compound for the treatment of RSV and/or IAV infections.