Senescence program and its reprogramming in pancreatic premalignancy.

Tumor is a representative of cell immortalization, while senescence irreversibly arrests cell proliferation. Although tumorigenesis and senescence seem contrary to each other, they have similar mechanisms in many aspects. Pancreatic ductal adenocarcinoma (PDA) is highly lethal disease, which occurs and progresses through a multi-step process. Senescence is prevalent in pancreatic premalignancy, as manifested by decreased cell proliferation and increased clearance of pre-malignant cells by immune system. However, the senescent microenvironment cooperates with multiple factors and significantly contributes to tumorigenesis. Evidently, PDA progression requires to evade the effects of cellular senescence. This review will focus on dual roles that senescence plays in PDA development and progression, the signaling effectors that critically regulate senescence in PDA, the identification and reactivation of molecular targets that control senescence program for the treatment of PDA.

Cytotoxic alkaloids from the twigs and leaves of Cephalotaxus sinensis.

Twelve new Cephalotaxus alkaloids (1-12) and nine known analogues (13-21) were isolated and identified from the twigs and leaves of Cephalotaxus sinensis. The structures of the new compounds (1-12) were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis. Cephalosine H (8) is the third example of an alkaloid containing the cephalolancine skeleton. Cephalosines J and K (10 and 11) are the rare natural Δ(2)1-alkene-6-hydroxyl homoerythrina-type alkaloids isolated from the Cephalotaxus genus. The racemization of cephalotaxine-type alkaloids is discussed. Alkaloids 6, 7, 11, 16, 18 and 19 exhibited broad and potent cytotoxicities against five human cancer cell lines, with IC50 values ranging from 0.053 to 10.720 µM, highlighting these compounds as promising leads for the development of new antitumor agents.

The mediating effect of sleep quality and fatigue between depression and renal function in nondialysis chronic kidney disease: a cross-sectional study.

BACKGROUND: Depressive symptoms, fatigue, and poor sleep quality are associated with renal function deterioration in patients with nondialysis chronic kidney disease (CKD-ND). This study was designed to examine whether fatigue and sleep quality are mediators of the association between depression and renal function. METHODS: This study adopted a cross-sectional study design. Patients with CKD-ND aged 20 years or older were recruited by purposive sampling at a medical center in Central Taiwan from December 2020 to July 2021. Data were collected using the Emotional and Social Support Scale, Fatigue Scale, Beck Depression Inventory-II (BDI-II), and Pittsburgh Sleep Quality Index. Medical records were reviewed to obtain the estimated glomerular filtration rate (eGFR) for the next month. The relationships among variables were analyzed using structural equation modeling to assess the goodness-of-fit of the model. Then, the bootstrapping method was used to analyze the mediated effect. RESULTS: Two hundred forty-two participants (mean age 70.5 years and 53% males) were included in the analysis. About 39% of the participants met the criteria for depressive symptoms in BDI-II, and 91% reported having sleep disturbances. Participants' degree of fatigue was not high (20.4 ± 13.3). The average eGFR was 25.45 mL/min/1.73 m 2 (± 13.36). The results showed that fatigue, sleep quality, and eGFR were significantly correlated with depression. The total effect size was - 0.8304 (95% confidence interval [CI], - 0.9602 to - 0.7006), and the indirect effect size was - 0.1738 (95% CI, - 0.2812 to - 0.0651), which was a statistically significant difference, indicating that the model has a mediating effect. According to mediation analysis, fatigue and sleep quality had a significant indirect effect on the relationship between depression and renal function (95% CI, - 0.0587 to - 0.0039). CONCLUSIONS: The findings suggest that fatigue and poor sleep quality may mediate the association between depression and renal function.

Connexin 43 mediated the angiogenesis of buyang huanwu decoction via vascular endothelial growth factor and angiopoietin-1 after ischemic stroke.

Buyang Huanwu decoction (BYHWD), a classical prescription for ischemic stroke, has been reported to promote angiogenesis after focal ischemia. However, the mechanisms of the contribution of BYHWD on angiogenesis are still unclear. Connexin 43 (Cx43) played important roles in the functions of neurogliovascular unit. Therefore, the aim of this study was to explore the potential role of Cx43 in angiogenesis of the ischemic brain after BYHWD treatment. Middle cerebral artery occlusion (MCAO) was used to establish the model of focal ischemia. BYHWD was administrated intragastrically twice a day after MCAO with or without Gap26 (a specific Cx43 inhibitor). Western blot, neurological deficits, immunofluorescent staining, and Evans blue dye were used to confirm the role of Cx43 in angiogenesis after BYHWD treatment. The expression levels of total Cx43 and phosphorylated Cx43 were upregulated by BYHWD and peaked at 7 days post MCAO. Inhibition of Cx43 with Gap26 significantly attenuated the protective role of BYHWD in neurological behavior. BYHWD treatment promoted angiogenesis demonstrated by increased microvascular density, upregulated vascular endothelial growth factor (VEGF), and angiopoietin-1 (Ang-1), while inhibition of Cx43 with Gap26 attenuated these effects of BYHWD. In addition, Gap26 inhibited the beneficial effect of BYHWD on blood-brain barrier (BBB) integrity. These results suggested that Cx43 mediated the angiogenesis of BYHWD via VEGF and Ang-1 after focal ischemic stroke.

Discovery of Prenyltransferase Inhibitors with In Vitro and In Vivo Antibacterial Activity.

Cis-prenyltransferases such as undecaprenyl diphosphate synthase (UPPS) and decaprenyl diphosphate synthase (DPPS) are essential enzymes in bacteria and are involved in cell wall biosynthesis. UPPS and DPPS are absent in the human genome, so they are of interest as targets for antibiotic development. Here, we screened a library of 750 compounds from National Cancer Institute Diversity Set V for the inhibition of Mycobacterium tuberculosis DPPS and found 17 hits, and then IC50s were determined using dose-response curves. Compounds were tested for growth inhibition against a panel of bacteria, for in vivo activity in a Staphylococcus aureus/Caenorhabditis elegans model, and for mammalian cell toxicity. The most active DPPS inhibitor was the dicarboxylic acid redoxal (compound 10), which also inhibited undecaprenyl diphosphate synthase (UPPS) as well as farnesyl diphosphate synthase. 10 was active against S. aureus, Clostridiodes difficile, Bacillus anthracis Sterne, and Bacillus subtilis, and there was a 3.4-fold increase in IC50 on addition of a rescue agent, undecaprenyl monophosphate. We found that 10 was also a weak protonophore uncoupler, leading to the idea that it targets both isoprenoid biosynthesis and the proton motive force. In an S. aureus/C. elegans in vivo model, 10 reduced the S. aureus burden 3 times more effectively than did ampicillin.