Heart rate deceleration and acceleration capacities associated with circadian rhythm of blood pressure in essential hypertension.

BACKGROUND: This study aimed to investigate the potential association between the circadian rhythm of blood pressure and deceleration capacity (DC)/acceleration capacity (AC) in patients with essential hypertension. METHODS: This study included 318 patients with essential hypertension, whether or not they were being treated with anti-hypertensive drugs, who underwent 24-hour ambulatory blood pressure monitoring (ABPM). Patients were categorized into three groups based on the percentage of nocturnal systolic blood pressure (SBP) dipping: the dipper, non-dipper and reverse dipper groups. Baseline demographic characteristics, ambulatory blood pressure monitoring parameters, Holter recordings (including DC and AC), and echocardiographic parameters were collected. RESULTS: In this study, the lowest DC values were observed in the reverse dipper group, followed by the non-dipper and dipper groups (6.46 ± 2.06 vs. 6.65 ± 1.95 vs. 8.07 ± 1.79 ms, P < .001). Additionally, the AC gradually decreased (-6.32 ± 2.02 vs. -6.55 ± 1.95 vs. -7.80 ± 1.73 ms, P < .001). There was a significant association between DC (r = .307, P < .001), AC (r=-.303, P < .001) and nocturnal SBP decline. Furthermore, DC (ß = 0.785, P = .001) was positively associated with nocturnal SBP decline, whereas AC was negatively associated with nocturnal SBP (ß = -0.753, P = .002). By multivariate logistic regression analysis, deceleration capacity [OR (95% CI): 0.705 (0.594-0.836), p < .001], and acceleration capacity [OR (95% CI): 1.357 (1.141-1.614), p = .001] were identified as independent risk factors for blood pressure nondipper status. The analysis of ROC curves revealed that the area under the curve for DC/AC in predicting the circadian rhythm of blood pressure was 0.711/0.697, with a sensitivity of 73.4%/65.1% and specificity of 66.7%/71.2%. CONCLUSIONS: Abnormal DC and AC density were correlated with a blunted decline in nighttime SBP, suggesting a potential association between the circadian rhythm of blood pressure in essential hypertension patients and autonomic nervous dysfunction.

Hit-to-Lead Optimization of the Natural Product Oridonin as Novel NLRP3 Inflammasome Inhibitors with Potent Anti-Inflammation Activity.

Targeting NLRP3 inflammasome with inhibitors is a novel strategy for NLRP3-driven diseases. Herein, hit compound 5 possessing an attractive skeleton was identified from our in-house database of oridonin, and then a potential lead compound 32 was obtained by optimization of 5, displaying two-digit nanomolar inhibition on NLRP3. Moreover, compound 32 showed enhanced safety index (SI) relative to oridonin (IC50 = 77.2 vs 780.4 nM, SI = 40.5 vs 8.5) and functioned through blocking ASC oligomerization and interaction of NLRP3-ASC/NEK7, thereby suppressing NLRP3 inflammasome assembly and activation. Furthermore, diverse agonists-induced activations of NLRP3 could be impeded by compound 32 without altering NLRC4 or AIM2 inflammasome. Crucially, compound 32 possessed tolerable pharmaceutical properties and significant anti-inflammatory activity in MSU-induced gouty arthritis model. Therefore, this work enriched the SAR of NLRP3 inflammasome inhibitors and provided a potential candidate for the treatment of NLRP3-associated diseases.

Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 µM) with pyrimidone compound 5 (GSK-3ß: IC50 = 3 µM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3ß (GSK-3ß). The optimal compound 18a possessed potent dual AChE/GSK-3ß inhibition (AChE: IC50 = 0.047 ± 0.002 µM, GSK-3ß: IC50 = 0.930 ± 0.080 µM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 µM. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.

Iodine-Promoted Reductive Sulfenylation Using Ketones as Hydride Donors.

Herein, an iodine-promoted reductive sulfenylation reaction of ketones with disulfides has been developed. This method provides an approach for synthesizing unsymmetrical alkyl-alkyl and alkyl-aryl sulfides in a single step. Investigation of the reaction mechanism revealed that ketones play a dual role in this process. They react with disulfides to produce vinyl thioethers and act as effective organic hydride donors, reducing the number of vinyl thioethers that are formed in situ. This study expands the range of applications of ketones in chemical synthesis.

Comparing surgical and endoscopic resection approaches for colorectal neuroendocrine tumors within the diameter range of 10-20mm: an inverse probability weighting analysis based on the SEER database.

Background: Currently, the primary treatment modalities for colorectal neuroendocrine tumors (CRNET) with a diameter between 10mm and 20mm are surgical resection (SR) and endoscopic resection (ER). However, it remains unclear which surgical approach yields the greatest survival benefit for patients. Methods: This study included data from patients diagnosed with CRNET with tumor diameters ranging from 10mm to 20mm between the years 2004 and 2019, obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were categorized into ER and SR groups based on the respective surgical approaches. Inverse probability weighting (IPTW) was employed to mitigate selection bias. Kaplan-Meier analysis and log-rank tests were utilized to estimate overall survival (OS) and cancer-specific survival (CSS). Cox regression analysis (univariate and multivariate) was performed to evaluate potential factors influencing survival. Results: A total of 292 CRNET patients were included in this study (ER group: 108 individuals, SR group: 184 individuals). Prior to IPTW adjustment, Kaplan-Meier analysis and Cox proportional hazard regression analysis demonstrated that the OS and CSS of the SR group were inferior to those of the ER group. However, after IPTW adjustment, no statistically significant differences in prognosis were observed between the two groups. Subgroup analyses revealed that patients with muscular invasion, positive lymph nodes, or distant metastasis derived greater survival benefits from SR. Significant differences in OS and CSS between the two groups were also observed across different age groups. Conclusion: For patients with mucosal-limited lesions and without local lymph node or distant metastasis, ER is the preferred surgical approach. However, for patients with muscular invasion or positive lymph nodes/distant metastasis, SR offers a better prognosis. The choice of surgical approach should be based on the specific clinical characteristics of patients within different subgroups.

Discovery of hematopoietic progenitor kinase 1 inhibitors using machine learning-based screening and free energy perturbation.

Hematopoietic progenitor kinase 1 (HPK1) is a key negative regulator of T-cell receptor (TCR) signaling and a promising target for cancer immunotherapy. The development of novel HPK1 inhibitors is challenging yet promising. In this study, we used a combination of machine learning (ML)-based virtual screening and free energy perturbation (FEP) calculations to identify novel HPK1 inhibitors. ML-based screening yielded 10 potent HPK1 inhibitors (IC50 < 1 µM). The FEP-guided modification of the in-house false-positive hit, DW21302, revealed that a single key atom change could trigger activity cliffs. The resulting DW21302-A was a potent HPK1 inhibitor (IC50 = 2.1 nM) and potently inhibited cellular HPK1 signaling and enhanced T-cell function. Molecular dynamics (MD) simulations and ADME predictions confirmed DW21302-A as candidate compound. This study provides new strategies and chemical scaffolds for HPK1 inhibitor development.Communicated by Ramaswamy H. Sarma.

Discovery of novel ß-elemene hybrids with hydrogen sulfide-releasing moiety possessing cardiovascular protective activity for the treatment of atherosclerosis.

Herein, a series of novel ß-elemene hybrids with different types of hydrogen sulfide (H2S) donors was designed and synthesized for the first time. In addition, all compounds were tested for H2S release in phosphate buffer solution assay, among which the derivatives with 5-p-hydroxyphenyl-3H-1,2-dithiole-3-thione (ADT-OH) as the H2S donor released the best level. The results of the isolated vasodilation assay revealed that all the compounds exhibited a degree of vasodilatory effect, and the representative compound "ß-elemene-H2S gas donor" hybrid L13-2h produced more than 50% vasodilatory activity at a concentration of 20 µM. Furthermore, L13-2h possessed good concentration dependence and significantly better vasodilatory activity than the lead compound L13. In the RAW 264.7 cellular lipid inhibition against oxidized low-density lipoprotein (ox-LDL) stimulation assay, eight compounds, including L13-2g and L13-2h, produced significant cellular lipid-lowering activity. The results of the further antioxidant activity study showed that the representative compounds L13-2g and L13-2h improved H2O2-induced oxidative damage in HUVEC cells and compound L13-2h exhibited excellent antioxidant damage protection activity compared to the positive control. Moreover, none of the target compounds appeared to be significantly cytotoxic at the tested concentrations. These results suggest that the hybridization of hydrogen sulfide donors with ß-elemene provides a promising approach for the discovery of novel anti-atherosclerotic drugs from natural products.

IRF4 induces M1 macrophage polarization and aggravates ulcerative colitis progression by the Bcl6-dependent STAT3 pathway.

Ulcerative colitis (UC) is an idiopathic chronic intestinal inflammation. An increasing body of evidence shows that macrophages play an important role in the pathogenesis of UC. Interferon regulatory factor 4 (IRF4) is crucial for the development of autoimmune diseases via regulating immune cells. This research was designed to explore the function of IRF4 in UC and its association with macrophage polarization. The in vitro model of UC was established by stimulating colonic epithelial cells with tumor necrosis factor α (TNF-α). A mouse model of UC was constructed by injecting C57BL/6 mice with dextran sulfate sodium salt. Flow cytometry was used to assess percentage of CD11b+ CD86+ and CD11b+ CD206+ cells in bone marrow macrophages. Occult blood tests were used to detect hematochezia. Hematoxylin and eosin staining assay was used to assess colon pathological changes. Enzyme-linked immunosorbent assay (ELISA) was used to detect concentrations of inflammatory cytokines. The interaction of IRF4 and B-cell lymphoma 6 (Bcl6) was confirmed using GST pull-down and coimmunoprecipitation assays. Our findings revealed that IRF4 promoted cell apoptosis and stimulated M1 macrophage polarization in vitro. Furthermore, IRF4 aggravated symptoms of the mouse model of UC and aggravated M1 macrophage polarization in vivo. IRF4 negatively regulated Bcl6 expression. Downregulation of Bcl6 promoted apoptosis and M1 macrophage polarization in the presence of IRF4 in vitro and in vivo. Moreover, Bcl6 positively mediated the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. In conclusion, IRF4 aggravated UC progression through promoting M1 macrophage polarization via Bcl6/JAK2/STAT3 pathway. These findings suggested that IRF4 might be a good target to competitively inhibit or to treat with UC.

Synergistic effects of ferulic acid esterase-producing lactic acid bacteria, cellulase and xylanase on the fermentation characteristics, fibre and nitrogen components and microbial community structure of Broussonetia papyrifera during ensiling.

BACKGROUND: The high fibre content of whole plants of Broussonetia papyrifera limits its efficient utilization. Ferulic acid esterase (FAE), in combination with xylanase, can effectively cleave the lignin-carbohydrate complex, promoting the function of cellulase. However, little is known about the impact of these additives on silage. To effectively utilize natural woody plant resources, FAE-producing Lactiplantibacillus plantarum RO395, xylanase (XY) and cellulase (CE) were used to investigate the dynamic fermentation characteristics, fibre and nitrogen components and microbial community structure during B. papyrifera ensiling. RESULTS: Broussonetia papyrifera was either not treated (CK) or treated with FAE-producing lactic acid bacteria (LP), CE, XY, LP + CE, LP + XY or LP + CE + XY for 3, 7, 15, 30 or 60 days, respectively. In comparison with those in the CK treatment, the L. plantarum and enzyme treatments (LP + CE, LP + XY and LP + XY + CE), especially the LP + XY + CE treatment, significantly increased the lactic acid concentration and decreased the pH and the contents of acid detergent insoluble protein and NH3 -N (P < 0.05). Enzyme addition improved the degradation efficiency of lignocellulose, and a synergistic effect was observed after enzyme treatment in combination with LP; in addition, the lowest acid detergent fibre, neutral detergent fibre, hemicellulose and cellulose contents were detected after the LP + CE + XY treatment (P < 0.05). Moreover, CE, XY and LP additions significantly improved the microbial community structure, increased the relative abundance of Lactiplantibacillus and Firmicutes, and effectively inhibited undesirable bacterial (Enterobacter) growth during ensiling. CONCLUSION: FAE-producing L. plantarum and the two tested enzymes exhibited synergistic effects on improving the quality of silage, which indicates that this combination can serve as an efficient method for improved B. papyrifera silage utilization. © 2023 Society of Chemical Industry.

Recent advances of vacuolar protein-sorting 34 inhibitors targeting autophagy.

Autophagy is a ubiquitous pathological/physiological antioxidant cellular reaction in eukaryotic cells. Vacuolar protein sorting 34 (Vps34 or PIK3C3), which plays a crucial role in autophagy, has received much attention. As the only Class III phosphatidylinositol-3 kinase in mammals, Vps34 participates in vesicular transport, nutrient signaling and autophagy. Dysfunctionality of Vps34 induces carcinogenesis, and abnormal autophagy mediated by dysfunction of Vps34 is closely related to the pathological progression of various human diseases, which makes Vps34 a novel target for tumor immunotherapy. In this review, we summarize the molecular mechanisms underlying macroautophagy, and further discuss the structure-activity relationship of Vps34 inhibitors that have been reported in the past decade as well as their potential roles in anticancer immunotherapy to better understand the antitumor mechanism underlying the effects of these inhibitors.

Preoperative radiotherapy does not improve and may even be detrimental to the long-term prognosis of patients diagnosed with stage III colon adenocarcinoma: a propensity score-matched SEER database analysis.

Background: Currently, for patients with colon adenocarcinoma who are diagnosed with local lymph node metastasis, it is typically recommended to undergo neoadjuvant treatment before undergoing curative surgical intervention. Nowadays, the focus of preoperative adjuvant therapy for colon adenocarcinoma patients mainly revolves around chemotherapy, and the impact of preoperative radiotherapy on long-term prognosis remains uncertain. Methods: We extracted data from the Surveillance, Epidemiology, and End Results database for patients with stage III colon adenocarcinoma between 2004 and 2019. Using propensity score matching (PSM), the patients were divided into a preoperative radiotherapy group and a non-preoperative radiotherapy group, and the differences in Kaplan-Meier (KM) survival curves between the two groups were compared. Cox regression analysis was employed to identify clinical factors that influence survival in stage III colon adenocarcinoma, and the prognostic differences between the two groups were compared within specific subgroups of these clinical factors. Results: After PSM, a total of 242 patients were included in the study, divided into the preoperative radiotherapy group and the non-preoperative radiotherapy group. There were no statistically significant differences in important clinical characteristics between the two groups. KM analysis revealed no statistically significant difference in overall survival (OS) between the two groups. Furthermore, age, chemotherapy, T staging, N staging, race, tumor grade, gender, tumor location, and tumor diameter were identified as important factors influencing the prognosis of patients. Within each level of the aforementioned subgroups, there were no differences in OS between the two groups. In fact, in specific subgroups, the non-preoperative radiotherapy group exhibited better OS than the preoperative radiotherapy group. Conclusion: Preoperative radiotherapy does not improve the long-term prognosis of patients with stage III colon adenocarcinoma. In certain patient populations with specific clinical characteristics, preoperative radiotherapy may even lead to a decrease in OS.

Iodine-promoted transfer of dihydrogen from ketones to alkenes, triphenylmethyl, and diphenylmethyl derivatives.

Herein, a novel class of transfer hydrogenation agent, cycloheptanone, was successfully employed in metal-free hydrogenation facilitated by iodine. A series of alkenes, triphenylmethyl derivatives, and diphenylmethyl derivatives were reduced to the desired compounds in moderate to excellent yields. The transfer hydrodeuteration of alkenes using α-deuterated cyclododecanone exhibited high regioselectivity. Preliminary mechanism studies confirmed the origins of the two hydrogen atoms involved in the reduction of alkenes. The current study paves the way for the use of ketones as unique transfer hydrogenation agents in chemical synthesis.

Design, synthesis and biological evaluation of novel dihydroquinolin-4(1H)-one derivatives as novel tubulin polymerization inhibitors.

A series of novel dihydroquinolin-4(1H)-one derivatives targeting colchicine binding site on tubulin were designed, synthesized and evaluated as anticancer agents. The most potent compound 6t showed remarkable antiproliferative activities against four cancer cell lines with IC50 values among 0.003-0.024 µM and tubulin polymerization inhibitory activity (IC50 = 3.06 µM). Further mechanism studies revealed that compound 6t could induce K562 cells apoptosis and arrest at the G2/M phase. Meanwhile, 6t significantly inhibited migration and invasion of MDA-MB-231 cells, and disrupted the angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro. In addition, compound 6t inhibited tumor growth in H22 allograft tumor model with a tumor growth inhibition (TGI) rate of 63.3 % (i.v., 20 mg/kg per day) without obvious toxicity. Collectively, these results indicated that compound 6t was a novel tubulin polymerization inhibitor with potent anticancer properties in vitro and in vivo.

Design, synthesis and biological evaluation of novel indanones derivatives as potent acetylcholinesterase/monoamine oxidase B inhibitors.

Aim: Based on a multitarget design strategy, a series of novel indanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Results: These compounds exhibited significant inhibitory activities against acetylcholinesterase (AChE) and moderate inhibitory activities toward monoamine oxidase B (MAO-B). The optimal compound A1 possessed excellent dual AChE/MAO-B inhibition both in terms of potency (AChE: IC50 = 0.054 ± 0.004 µM; MAO-B: IC50 = 3.25 ± 0.20 µM), moderate inhibitory effects on self-mediated amyloid-ß (Aß) aggregation and antioxidant activity. In addition, compound A1 exhibited low neurotoxicity. More importantly, compound A1 showed significant cognitive and spatial memory improvements in the scopolamine-induced AD mouse model. Conclusion: All results suggest that compound A1 may become a promising lead of anti-AD drug for further development.

Luminescence properties and energy-transfer behavior of Y2-x-yBixEuyMgTiO6 phosphors.

In recent years, double perovskite has become a research hotspot of luminescent matrix materials due to its flexible structure, easy doping and good thermal stability. By using a high temperature solid-state technique, Bi3+ and Eu3+ co-doped Y2-x-yBixEuyMgTiO6 (0 ≤ x ≤ 0.1, 0 ≤ y ≤ 0.5) phosphors were made. X-ray diffraction (XRD) analysis shows that the crystal structure of all samples is monoclinic system, P21/n; Bi3+ and Eu3+ can be doped into the position of Y3+ in the substitution system of Y2MgTiO6. Both photoluminescence spectroscopy (PL) and X-ray excitation luminescence spectroscopy (XEL) were used to investigate the link between Bi3+ and Eu3+ doping concentrations and luminescence intensity. PL shows that: When 375 nm is used as the excitation wavelength, by varying the doping concentration of Eu3+ in the Y1.995-yBi0.005EuyMgTiO6 phosphor, it is possible to create the color-tunable emission from blue to red; The introduction of an appropriate amount of Bi3+ will increase the typical Eu3+ emission; The way that the system's Bi3+ and Eu3+ exchange energy can be observed by combining the fluorescence decay curve and photoluminescence. Fitting by concentration quenching model shows that the resonant dipole-dipole transition is the mechanism of energy transfer between Bi3+→Eu3+; X-rays may successfully stimulate the phosphor, and the spectral distribution of XEL and PL is basically the same; The introduction of an appropriate amount of Bi3+ is also beneficial to improving the sensitivity of XEL; Changes in temperature affect the sample's emission intensity; In addition, the samples remain stable for an extended period while being continuously exposed to X-rays at various environmental temperatures. The a forementioned findings suggest that the phosphor has potential use value in the lighting industry, X-ray imaging and temperature sensor.

Small-Molecule Hydrophobic Tagging: A Promising Strategy of Druglike Technology for Targeted Protein Degradation.

Targeted protein degradation (TPD) technologies have catalyzed a paradigm shift in therapeutic strategies and offer innovative avenues for drug design. Hydrophobic tags (HyTs) are bifunctional TPD molecules consisting of a ″lipophilic small-molecule tags″ group and a small-molecule ligand for the target protein. Despite the vast potential of HyTs, they have received relatively limited attention as a promising frontier. Leveraging their lower molecular weight and reduced numbers of hydrogen bond donors/acceptors (HBDs/HBAs) in comparison with proteolysis-targeting chimeras (PROTACs), HyTs present a compelling approach for enhancing druglike properties. In this Perspective, we explore the diverse range of HyT structures and their corresponding degradation mechanisms, thereby illuminating their broad applicability in targeting a diverse array of proteins, including previously elusive targets. Moreover, we scrutinize the challenges and opportunities entailed in developing this technology as a viable and fruitful strategy for drug discovery.

Controlled release of MT-1207 using a novel gastroretentive bilayer system comprised of hydrophilic and hydrophobic polymers.

In the present study, novel gastroretentive bilayer tablets were developed that are promising for the once-a-day oral delivery of the drug candidate MT-1207. The gastroretentive layer consisted of a combination of hydrophilic and hydrophobic polymers, namely polyethylene oxide and Kollidon® SR. A factorial experiment was conducted, and the results revealed a non-effervescent gastroretentive layer that, unlike most gastroretentive layers reported in the literature, was easy to prepare, and provided immediate tablet buoyancy (mean floating lag time of 1.5 s) that lasted over 24 h in fasted state simulated gastric fluid (FaSSGF) pH 1.6, irrespective of the drug layer, thereby allowing a 24-hour sustained release of MT-1207 from the drug layer of the tablets. Furthermore, during in vitro buoyancy testing of the optimised bilayer tablets in media of different pH values (1.0, 3.0, 6.0), the significant difference (one-way ANOVA, p < 0.001) between the respective total floating times indicated that stomach pH effects on tablet buoyancy are important to be considered during the development of non-effervescent gastroretentive formulations and the choice of dosing regimen. To the best of our knowledge, this has not been reported before, and it should probably be factored in when designing dosing regimens. Finally, a pharmacokinetic study in Beagle dogs indicated a successful in vivo 24-hour sustained release of MT-1207 from the optimised gastroretentive bilayer tablet formulations with the drug plasma concentration remaining above the estimated minimum effective concentration of 1 ng/mL at the 24-hour timepoint and also demonstrated the gastroretentive capabilities of the hydrophilic and hydrophobic polymer combination. The optimised formulations will be forwarded to clinical development.

Glycemic status and its association with retinal age gap: Insights from the UK biobank study.

OBJECTIVE: To investigate associations between different glycemic status and biological age indexed by retinal age gap. METHODS: A total of 28,919 participants from the UK Biobank study with available glycemic status and qualified retinal imaging data were included in the present analysis. Glycemic status included type 2 diabetes mellitus (T2D) disease status and glycemic indicators of plasma glycated hemoglobin (HbA1c) and glucose. Retinal age gap was defined as the difference between the retina-predicted age and chronological age. Linear regression models estimated the association of different glycemic status with retinal age gap. RESULTS: Prediabetes and T2D was significantly associated with higher retinal age gaps compared to normoglycemia (regression coefficient [ß] = 0.25, 95% confidence interval [CI]: 0.11-0.40, P = 0.001; ß = 1.06, 95% CI: 0.83-1.29, P < 0.001; respectively). Multi-variable linear regressions further found an increase of HbA1c was independently associated with higher retinal age gaps among all subjects or subjects without T2D. Significant positive associations were noted across the increasing HbA1c and glucose groups with retinal age gaps compared to the normal level group. These findings remained significant after excluding diabetic retinopathy. CONCLUSIONS: Dysglycemia was significantly associated with accelerated ageing indexed by retinal age gaps, highlighting the importance of maintaining glycemic status.

Synthesis and bioevaluation of novel stilbene-based derivatives as tubulin/HDAC dual-target inhibitors with potent antitumor activities in vitro and in vivo.

A series of novel stilbene-based derivatives were designed and synthesized as tubulin/HDAC dual-target inhibitors. Among forty-three target compounds, compound II-19k not only exhibited considerable antiproliferative activity in the hematological cell line K562 with IC50 value of 0.003 µM, but also effectively inhibited the growth of various solid tumor cell lines with IC50 values ranging from 0.005 to 0.036 µM. The mechanism studies demonstrated that II-19k could inhibit microtubules and HDACs at the cellular level, block cell cycle arrest at G2 phase, induce cell apoptosis, and reduce solid tumor cells metastasis. What's more, the vascular disrupting effects of compound II-19k were more pronounced than the combined administration of parent compound 8 and HDAC inhibitor SAHA. The in vivo antitumor assay of II-19k also showed the superiority of dual-target inhibition of tubulin and HDAC. II-19k significantly suppressed the tumor volume and effectively reduced tumor weight by 73.12% without apparent toxicity. Overall, the promising bioactivities of II-19k make it valuable for further development as an antitumor agent.

Prediction of distant metastasis and specific survival prediction of small intestine cancer patients with metastasis: A population-based study.

BACKGROUND: Small intestine cancer (SIC) is difficult to diagnose early and presents a poor prognosis due to distant metastasis. This study aimed to develop nomograms for diagnosing and assessing the prognosis of SIC with distant metastasis. METHODS: Patients diagnosed with SIC between 2010 and 2015 were included from the Surveillance, Epidemiology and End Results database. Univariate and multifactor analysis determined independent risk factors for distant metastasis and prognostic factors for overall and cancer-specific survival. We then constructed the corresponding three nomograms and assessed the diagnostic accuracy of the nomograms by net reclassification improvement, receiver operating characteristic curves and calibration curves, assessed the clinical utility by decision curve analysis. RESULTS: The cohort consisted of 6697 patients, of whom 1299 had distant metastasis at diagnosis. Tstage, Nstage, age, tumor size, grade, and histological type were independent risk factors for distant metastasis. Age, histological type, T stage, N stage, grade, tumor size, whether receiving surgery, number of lymph nodes removed, and the presence of bone or lung metastases were predictors of both overall survival and cancer-specific survival. The nomograms showed excellent accuracy in predicting distant metastasis and prognosis. CONCLUSION: Nomograms were developed and validated for SIC patients with distant metastasis, aiding physicians in making rational and personalized clinical decisions.