The association between new inflammation markers and frequent peritoneal dialysis-associated peritonitis.

OBJECTIVE: To validate an association between new inflammation and frequent peritoneal dialysis-associated peritonitis (PDAP). MATERIALS AND METHODS: In China, retrospective clinical data were collected on 208 patients who received continuous ambulatory peritoneal dialysis (CAPD) between 2010 and 2021. The patients were divided into two groups: non-frequent PDAP (the interval between two peritonitis episodes of more than one year) and frequent PDAP (the interval between two peritonitis episodes of less than one year). Patients with their first episode of peritonitis had their age, gender, history of hypertension, diabetic disease, underlying renal disease, bacterial infection, and laboratory data collected. The outcomes of bacterial dispersion, systemic immune-inflammation index (SII), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), and risk variables associated with frequent PDAP were analyzed. RESULTS: There are differences between the two groups in dialysis time (p = 0.006), hypertensive nephropathy (p = 0.038), staphylococcus (p = 0.035), white blood cells (p = 0.001), neutrophil (p < 0.01), lymphocyte (p < 0.01), platelet(p = 0.01), SII(p < 0.01), CRP/HDL-C (p = 0.002), CRP (p < 0.001), serum creatinine (p = 0.007), blood urea nitrogen (p = 0.05), serum magnesium (0.03), serum potassium (p = 0.007), and dialysate polymorphonuclear cells (p = 0.004). Multifactorial logistic regression analysis found that SII (p < 0.001), CRP/HDL-C (p = 0.041), and Diabetes mellitus (p = 0.027) were independent risk factors for frequent PDAP. The ROC curve analysis revealed that combining SII with CRP/HDL-C resulted in the largest AUC area (AUC = 0.814). CONCLUSIONS: Our findings offer clinical proof of the combination of SII and CRP/HDL-C in patients with frequent PDAP.

Development of VER-50589 analogs as novel Hsp90 inhibitors.

As an important target for tumor therapy, heat shock protein 90 has attracted tremendous attention. Through structure analysis, we rationally designed three analogs of VER-50589 which is a known and potent Hsp90 inhibitor. Target inhibitory activity result showed that one compound dubbed as 12-1 exhibited strong inhibitory activity against Hsp90 with an IC50 value of 9 nM. In tumor cell viability experiment, compound 12-1 robustly repressed the proliferation against six human tumor cells with IC50 values all in nanomolar range scoring over VER-50589 and geldanamycin. 12-1 was able to induce apoptosis of tumor cells and arrest the tumor cell cycle in G0/G1 phase. Meanwhile, western blot results showed that 12-1 could significantly downregulated the expression of two Hsp90 client proteins CDK4 and HER2. Finally, molecular dynamic simulation showed that compound 12-1 could fit well with ATP binding site on N-terminal of Hsp90.

Discovery and SAR analysis of phenylbenzo[d][1,3]dioxole-based proprotein convertase subtilisin/kexin type 9 inhibitors.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapeutic target for the development of cholesterol-lowering drugs. In the discovery of PCSK9/LDLR (low-density lipoprotein receptor) protein-protein interaction (PPI) impairing small molecules, a total of 47 phenylbenzo[d][1,3] dioxole-based compounds were designed and synthesised. The result revealed that the 4-chlorobenzyl substitution in the amino group is important for the PPI disrupting activity. In the hepatocyte-based functional tests, active compounds such as A12, B1, B3, B4 and B14, restored the LDLR levels on the surface of hepatic HepG2 cells and increased extracellular LDL uptake in the presence of PCSK9. It is notable that molecule B14 exhibited good performance in all the evaluations. Collectively, novel structures targeting PCSK9/LDLR PPI have been developed with hypolipidemic potential. Further structural modification of derived active compounds is promising in the discovery of lead compounds with improved activity for the treatment of hyperlipidaemia-related disorders.

Discovery and SAR analysis of 5-chloro-4-((substituted phenyl)amino)pyrimidine bearing histone deacetylase inhibitors.

Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. In the discovery of novel HDAC inhibitors with anticancer potency, the 5-chloro-4-((substituted phenyl)amino)pyrimidine fragment is assembled as a cap group into the structure of HDAC inhibitors. The SAR revealed that presence of small groups (such as methoxy substitution) is beneficial for the HDAC inhibitory activity. In the enzyme inhibitory selectivity test, compound L20 exhibited class I selectivity with IC50 values of 0.684 µM (selectivity index of >1462), 2.548 µM (selectivity index of >392), and 0.217 µM (selectivity index of >4608) against HDAC1, HDAC2 and HDAC3 compared with potency against HDAC6 (IC50 value of >1000 µM), respectively. In the antiproliferative assay, compound L20 showed both hematological and solid cancer inhibitory activities. In the flow cytometry, L20 promoted G0/G1 phase cell cycle arrest and apoptosis of K562 cells.

Chlorinated Flame-Retardant Dechlorane 602 Potentiates Type 2 Innate Lymphoid Cells and Exacerbates Airway Inflammation.

Chlorinated flame-retardant dechloranes are emerging substitutes for restricted flame retardants. Recent studies have demonstrated that they are accumulated in wildlife and detectable in humans; however, their effects on human health are poorly understood. Here, for the first time, we revealed that widely used chlorinated flame-retardant dechlorane 602 (Dec 602) exacerbated airway inflammation in two mouse models induced by house dust mite (HDM) or IL-33, respectively. Deteriorated airway inflammation by Dec 602 was associated with a higher production of type 2 cytokines including IL-4, IL-5, and IL-13, and IgE, accompanied by enhanced mRNA expression of proinflammatory cytokines such as TNF-α and IL-6. Mechanistically, we found that Dec 602 directly potentiated mouse and human group 2 innate lymphoid cells and, as such, promoted airway inflammation even in the absence of conventional T cells in Rag -/- mice. These findings provide novel immunological insights necessary for further studies of the health impact of emerging flame-retardant dechloranes including Dec 602.

Preparative Separation of Monoterpenoid Indole Alkaloid Epimers from Ervatamia yunnanensis Tsiang by pH-Zone-Refining Counter-Current Chromatography Combined with Preparative High-Performance Liquid Chromatography.

An effective method was developed for the preparative separation and purification of monoterpenoid indole alkaloid epimers from Ervatamia yunnanensis Tsiang using a combination of pH-zone-refining counter-current chromatography and preparative high-performance liquid chromatography. With this method, two pairs of MIA epimers including ervatamine (72 mg, 1), 20-epi-ervatamine (27 mg, 4), dregamine (95 mg, 2), tabernaemontanine (129 mg, 3), along with two MIAs, apparicine (112 mg, 5) and isovoacangine (15 mg, 6), were successfully purified from 2.1 g crude extract of E. yunnanensis, each with a purity of over 95% as determined by HPLC. The structures of the MIAs were identified by ESI-MS, 1D, and 2D NMR.

A novel monoterpenoid indole alkaloid with anticancer activity from Melodinus khasianus.

A novel monoterpenoid indole alkaloid with unprecedented 6/5/6/4/6 fused rings, khasuanine A (1), was isolated from the roots of Melodinus khasianus. The structure was determined by extensive analysis of its HR-MS, 1D-, and 2D-NMR spectra. Khasuanine A markedly inhibited the proliferation of PC3 cell with IC50 value of 0.45µM. Further study showed that khasuanine A was able to induce the apoptosis of PC3 cells by activation of caspase 3 and p53, and by inhibition of Bcl-2.

Design, synthesis and preliminary evaluation of α-sulfonyl γ-(glycinyl-amino)proline peptidomimetics as matrix metalloproteinase inhibitors.

A series of novel α-sulfonyl γ-(glycinyl-amino)proline peptidomimetic derivatives were designed, synthesized and assayed for their activities against matrix metalloproteinase-2 (MMP-2), aminopeptidase N (APN)/CD13 and HDACs. The results indicated that all the compounds exhibited highly selective inhibition against MMP-2 as compared with APN and HDACs. The antiproliferative activities of some compounds against SKOV3, HL60 and A549 cells were also investigated. Comparing with the control LY52, compound 12u, with excellent activity both in the enzymatic inhibition assay and cell-based assay, could be used as lead compound for the further development of MMP inhibitors.

Tanshinol ameliorates imiquimod-induced psoriasis by inhibiting M1 macrophage polarization through suppression of the notch signaling pathway.

BACKGROUND: Psoriasis is a common immune-related chronic inflammatory skin disease, often accompanied by significant itching, and once diseased, the course of the disease lasts for most of the lifetime. Tanshinol (TAN) is an active ingredient of Salvia miltiorrhiza, which possesses pharmacological effects such as anti-inflammatory and antioxidant properties. However, the effects of TAN on psoriasis have not been widely reported. Therefore, the aim of this study was to investigate the therapeutic effects and mechanisms of TAN in psoriasis. METHODS: An imiquimod (IMQ)-induced psoriasis mouse model was constructed and treated with different doses of TAN to observe the changes in skin lesion phenotype, macrophage polarization, inflammation and Notch signaling pathway in mice. Further removal of macrophages or inhibition or activation of Notch signaling pathway was performed to examine the changes in skin lesion phenotype, macrophage polarization, inflammation and Notch signaling pathway in mice. In addition, in vitro experiments verified that TAN regulates RAW264.7 macrophage polarization and cytokine secretion through the Notch pathway. RESULTS: The results showed that TAN alleviated IMQ-induced skin lesions and pathological phenotypes in psoriasis mice and inhibited Notch signaling pathway and M1-type macrophage polarization. Moreover, macrophage clearance and Notch signaling pathway activation inhibited the effect of TAN on psoriasis. Further in vitro experiments showed that Notch agonists reversed the effects of TAN on macrophage polarization and inflammatory cytokines. CONCLUSIONS: Collectively, these findings suggest that TAN may exert a therapeutic effect on psoriasis by inhibiting the Notch signaling pathway and thus M1-type macrophage polarization.

Design, synthesis and preliminary activity evaluation of novel 3-amino-2-hydroxyl-3-phenylpropanoic acid derivatives as aminopeptidase N/CD13 inhibitors.

Aminopeptidase N (APN/CD13) over expressed on tumour cells, plays a critical role in tumour invasion, metastasis and tumour angiogenesis. In this article, we described the design, synthesis and preliminary activity studies of novel 3-amino-2-hydroxyl-3-phenylpropanoic acid derivatives as APN inhibitors. The in vitro enzymatic inhibitions on APN from porcine kidney showed that compound 7e had the most potent inhibitory activity against APN with the IC(50) value to 1.26 ± 0.01 µM, which is better than that of bestatin (IC(50) = 2.55 ± 0.11 µM). In addition, compound 7e also showed better inhibitory activity against APN on human ovary clear cell carcinoma cell ES-2 than bestatin with the IC(50) value to 30.19 ± 1.02 µM versus 60.61 ± 0.1 µM. Compound 7e could be used as the lead compound in the future for anti-cancer agent research.

Effects of oral intake fruit or fruit extract on skin aging in healthy adults: a systematic review and Meta-analysis of randomized controlled trials.

Background: In recent years, oral various fruits or supplements of fruits natural extracts have been reported to have significant anti-aging effects on the skin (1, 2), However, despite many studies on this topic, there is often no clear evidence to support their efficacy and safety. In this paper, we present a comprehensive review and Meta-analysis of the evidence for the safety and efficacy of oral fruits and fruits extracts in improving skin aging. Methods: Four databases, Pubmed, Embase, Web of Science, and Cochrane Library (CENTRAL), were searched for relevant literature from 2000-01 to 2023-03. Seven randomized controlled trials (RCTs) of fruit intake or fruit extracts associated with anti-skin aging were screened for Meta-analysis. Results: Compared to placebo, oral intake of fruit or fruit extracts showed significant statistical differences in skin hydration and transepidermal water loss (TEWL), with a significant improvement in skin hydration and a significant decrease in TEWL. No significant statistical difference was observed in minimal erythema dose (MED), overall skin elasticity (R2), or wrinkle depth, and no evidence of significant improvement in skin condition was observed. Conclusion: Meta-analysis results suggest that consume administration of fruits or fruit extracts significantly enhances skin hydration and reduces transcutaneous water loss, but there is insufficient evidence to support other outcome recommendations, including minimal erythema dose (MED), overall skin elasticity(R2), and wrinkle depth. Systematic Review Registration: PROSPERO (york.ac.uk), identifier CRD42023410382.

Machine learning-based prediction of cerebral hemorrhage in patients with hemodialysis: A multicenter, retrospective study.

Background: Intracerebral hemorrhage (ICH) is one of the most serious complications in patients with chronic kidney disease undergoing long-term hemodialysis. It has high mortality and disability rates and imposes a serious economic burden on the patient's family and society. An early prediction of ICH is essential for timely intervention and improving prognosis. This study aims to build an interpretable machine learning-based model to predict the risk of ICH in patients undergoing hemodialysis. Methods: The clinical data of 393 patients with end-stage kidney disease undergoing hemodialysis at three different centers between August 2014 and August 2022 were retrospectively analyzed. A total of 70% of the samples were randomly selected as the training set, and the remaining 30% were used as the validation set. Five machine learning (ML) algorithms, namely, support vector machine (SVM), extreme gradient boosting (XGB), complement Naïve Bayes (CNB), K-nearest neighbor (KNN), and logistic regression (LR), were used to develop a model to predict the risk of ICH in patients with uremia undergoing long-term hemodialysis. In addition, the area under the curve (AUC) values were evaluated to compare the performance of each algorithmic model. Global and individual interpretive analyses of the model were performed using importance ranking and Shapley additive explanations (SHAP) in the training set. Results: A total of 73 patients undergoing hemodialysis developed spontaneous ICH among the 393 patients included in the study. The AUC of SVM, CNB, KNN, LR, and XGB models in the validation dataset were 0.725 (95% CI: 0.610 ~ 0.841), 0.797 (95% CI: 0.690 ~ 0.905), 0.675 (95% CI: 0.560 ~ 0.789), 0.922 (95% CI: 0.862 ~ 0.981), and 0.979 (95% CI: 0.953 ~ 1.000), respectively. Therefore, the XGBoost model had the best performance among the five algorithms. SHAP analysis revealed that the levels of LDL, HDL, CRP, and HGB and pre-hemodialysis blood pressure were the most important factors. Conclusion: The XGB model developed in this study can efficiently predict the risk of a cerebral hemorrhage in patients with uremia undergoing long-term hemodialysis and can help clinicians to make more individualized and rational clinical decisions. ICH events in patients undergoing maintenance hemodialysis (MHD) are associated with serum LDL, HDL, CRP, HGB, and pre-hemodialysis SBP levels.

Low-dose IL-2 Treatment Rescues Cognitive Deficits by Repairing the Imbalance Between Treg and Th17 Cells at the Middle Alzheimer's Disease Stage.

Multiple studies highlight the role of effector and regulatory CD4+T cells in the pathophysiology of Alzheimer's disease, and foster low-dose IL-2 treatment which induces regulatory CD4+T (Treg) cells expansion and activation as a promising strategy for its treatment. However, studies demonstrating discrepant Treg functions in AD have been reported. In addition, a compromised immune system associated with aging may substantially impact on these processes. Here, we report that there is an altered balance of activity between Treg cells and IL-17-producing helper T (Th17) cells in periphery and brain of APP/PS1 mice along the disease progression. A dramatic loss of the healthy balance of activity between Treg and Th17 cells was found at the middle disease stage. While peripheral low-dose recombinant human IL-2 administration could selectively modulate the abundance of Treg cells and repair the imbalance between Treg and Th17 subsets at the middle disease stage. We further show that modulation of peripheral immune balance through low-dose IL-2 treatment reduces the neuro-inflammation and increases numbers of plaque-associated microglia, accompanied by marked reduction of Aß plaque deposition and slower cognitive declines in APP/PS1 mice at the middle disease stage. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of the homeostasis of CD4+T cell subsets in Alzheimer's disease at the middle disease stage.

A novel aminopeptidase N inhibitor developed by virtual screening approach.

A virtual screening was performed to discover novel lead structures as potent aminopeptidase N(APN) inhibitors. A commercial database containing about 1,60,000 molecules in SPECS was filtered by rule of five, zinc binding groups, pharmacophore models and binding pattern analysis. At last, 24 molecules were selected for enzyme inhibition assay and compound 2 exhibited the inhibition constant (K(i)) of 2.79±0.32 µM against APN compared with Bestatin (K(i)= 3.37±0.24 µM). Our results indicated that compound 2 exhibited good antiproliferative activities against a broad spectrum of human cancer cell lines, and induced cell cycle arrest at G1 phase and eventual apoptosis. Moreover, compound 2 can inhibit the invasion of MDA-MB-231 cells. In summary, our results suggest that compound 2, a potent APN inhibitor, is worthy of further development.

Thrombospondin-1 short hairpin RNA suppresses tubulointerstitial fibrosis in the kidney of ureteral obstruction by ameliorating peritubular capillary injury.

BACKGROUND/AIMS: Thrombospondin-1 (TSP-1), a naturally occurring inhibitor of angiogenesis, is an important mediator of renal fibrosis in clinical and experimental kidney disease. Increasing evidence shows that the microvasculature plays a critical role in progressive renal disease. The present study was undertaken to investigate whether interstitial fibrosis could be prevented by abolishing TSP-1 function in unilateral ureteral obstruction (UUO)-induced renal fibrosis. METHODS AND RESULTS: A short hairpin RNA vector, designated Thbs-1, significantly suppressed TSP-1 in both transcriptional and translational levels in in vitro-cultured cells and in vivo fibrosis-induced mouse kidney. Furthermore, TSP-1 RNA interference increased the protein level of vascular endothelial growth factor (VEGF) and the density of peritubular capillaries (PTCs), reduced the expression of hypoxia-inducible factor-1α in tubulointerstitial cells, and collagen III and the connective tissue growth factor expression were markedly reduced from day 7 after UUO-induced fibrosis, but un- or vector-treated mice maintained their expression. TSP-1 shRNA suppressed the protein level of TSP-1, increased VEGF expression and PTC density and alleviated the development of renal interstitial fibrosis in UUO mice. CONCLUSION: These data suggest that inhibition of TSP-1 expression prevented tubulointerstitial fibrosis through ameliorating PTC injury.

Discovery of 2-Phenylquinoline-4-Carboxylic Acid Derivatives as Novel Histone Deacetylase Inhibitors.

Inhibition of histone deacetylases (HDACs) has been extensively studied in the development of anticancer drugs. In the discovery of potent HDAC inhibitors with novel structures, the 2-substituted phenylquinoline-4-carboxylic acid group was introduced to the cap moiety of HDAC inhibitors. In total, 30 compounds were synthesized with hydroxamic acid or hydrazide zinc-binding groups. In the enzyme inhibitory test, active compound D28 and its analog D29 exhibited significant HDAC3 selectivity against HDAC1, 2, 3, and 6. However, compared with D28, the hydrazide-bearing compounds (D29 and D30) with remarkably improved enzyme inhibitory activities did not exhibit significant antiproliferative potency in the in vitro anticancer study. Further K562 cell-based mechanistic results revealed that induction of G2/M cell cycle arrest and promotion of apoptosis make important contributions to the anticancer effects of molecule D28. Collectively, an HDAC3 selective inhibitor (D28) with potent in vitro anticancer activity was developed as a lead compound for the treatment of cancer.

Discovery of a potent olaparib-chlorambucil hybrid inhibitor of PARP1 for the treatment of cancer.

Introduction: Development of Poly (ADP-ribose) polymerase (PARP) inhibitors has been extensively studied in cancer treatment. Olaparib, the first approved PARP inhibitor, showed potency in the inhibition of both BRCA (breast cancer associated)-mutated and BRCA-unmutated cancers. Methods: Aiming to the discovery of olaparib analogs for the treatment of cancer, structural modifications were performed based on the scaffold of olaparib. In the first series, reduction of carbonyl group to CH2 led to decrease of PARP1 inhibitory activity. Preserving the original carbonyl group, molecules with potent PARP1 inhibitory activities were derived by introduction of hydrazide and aromatic nitrogen mustard groups. The synthesized compounds were evaluated in the in the PARP1 enzyme inhibitory screening, cancer cell based antiproliferative assay, cell cycle arrest and apoptosis studies. Results: It is remarkable that, molecule C2 with chlorambucil substitution, exhibited potent PARP1 inhibitory activity and a broad-spectrum of anticancer potency in the in vitro antiproliferative assay. Compared with olaparib and chlorambucil, molecule C2 also showed significant potency in inhibition of a variety of BRCA-unmutated cell lines. Further analysis revealed the effects of C2 in induction of G2/M phase cell cycle arrest and promotion of apoptosis. Discussion: Collectively, the olaparib-chlorambucil hybrid molecule (C2) could be utilized as a lead compound for further drug design.

Novel antileukemic agents derived from tamibarotene and nitric oxide donors.

A series of novel nitric oxide-releasing tamibarotene derivatives were synthesized by coupling nitric oxide (NO) donors with tamibarotene via various spacers, and were evaluated for their antiproliferative activities against human leukemic HL-60, NB4 and K562 cell lines in vitro. The test results showed that three compounds (7g, 9a and 9e) exhibited more potent antileukemic activity than the control tamibarotene. Furthermore, the preliminary structure-activity analysis revealed that amino acids serving as spacers could bring about significantly improved biological activities of NO donor hybrids. These interesting results could provide new insights into the development of NO-based antileukemic agents.

Design, synthesis and biological evaluation of tyrosine-based hydroxamic acid analogs as novel histone deacetylases (HDACs) inhibitors.

Histone deacetylases (HDACs) are a promising target for treating cancer and some other disorders. Herein, based on the structure of our previously reported tetrahydroisoquinoline-based hydroxamic acids, a novel series of tyrosine-based hydroxamic acid derivatives was designed and synthesized as HDACs inhibitors. Compared with tetrahydroisoquinoline-based hydroxamic acids, tyrosine-based hydroxamic acid derivatives exhibited more potent HDAC8 inhibitory activity. However, the antiproliferative activities and HeLa cell nuclear extract inhibition of several selected tyrosine-based hydroxamic acids were moderate.