Natural products fragment-based design and synthesis of a novel pentacyclic ring system as potential MAPK inhibitor.

The synthesis of compounds based on fragments derived from natural products (NPs) serves as a source of inspiration for the design of pseudo-natural products (PNPs), to identify bioactive molecules that exhibit similar characteristics to NPs. These novel molecular scaffolds exhibit previously unexplored biological activities as well. This study reports the development and synthesis of a novel pentacyclic ring system, the indole-pyrimidine-quinoline (IPQ) scaffold. The design of this scaffold was based on the structural characteristics of four natural products, namely tryptanthrin, luotonin A, rutaecarpine, and camptothecin. Several successive steps accomplished the effective synthesis of the IPQ scaffold. The constituent components of the pentacycle, containing the indole, quinazolinone, pyrimidone, and quinoline units, possess significant biological significance. Compound 1a demonstrated noteworthy anti-tumor activity efficacy against A549 cell lines among the tested compounds. The compound 1a was observed to elicit cell cycle arrest in both the G2/M and S phases, as well as trigger apoptosis in A549 cells. These effects were attributed to its ability to modulate the activation of mitochondrial-related mitogen-activated protein kinase (MAPK) signaling pathways.

Synthesis and Antifungal Properties of 1,2,4-Triazole Schiff Base Agents Based on a 3D-QSAR Model.

Based on our previous research, a 3D-QSAR model (q2=0.51, ONC=5, r2=0.982, F=271.887, SEE=0.052) was established to predict the inhibitory effects of triazole Schiff base compounds on Fusarium graminearum, and its predictive ability was also confirmed through the statistical parameters. According to the results of the model design, 30 compounds with superior bioactivity compared to the template molecule 4 were obtained. Seven of these compounds (DES2-6, DES9-10) with improved biological activity and readily available raw materials were successfully synthesized. Their structures were confirmed through HRMS, NMR, and single crystal X-ray diffraction analysis (DES-5). The bioactivity of the final products was investigated through an in vitro antifungal assay. There was little difference in the EC50 values between the experimental and predicted values of the model, demonstrating the reliability of the model. Especially, DES-3 (EC50=9.915 mg/L) and DES-5 (EC50=9.384 mg/L) exhibited better inhibitory effects on Fusarium graminearum compared to the standard drug (SD) triadimenol (EC50=10.820 mg/L). These compounds could serve as potential new fungicides for future research. The interaction between the final products and isocitrate lyase (ICL) was investigated through molecular docking. Compounds with R groups that have a higher electron-donating capacity were found to be biologically active.

Molecular recognition and binding between human plasminogen Kringle 5 and α-chain of human complement component C3b by frontal chromatography and dynamics simulation.

The binding and molecular recognition between α-chain of human complement C3b (α-chain of C3b) and human plasminogen Kringle 5 (Kringle 5) were studied and explored by frontal chromatography and dynamics simulation in the combination of bio-specific technologies. The specific interaction between the α-chain of C3b and Kringle 5 was initially confirmed by ligand blot and ELISA (Kd = 4.243×10-6 L/mol). Furthermore, the binding determination conducted via frontal chromatography showed that the presence of a single binding site between them, with the binding constant of 2.98 × 105 L/mol. Then the molecular recognition by dynamics simulation and molecular docking showed that there were 9 and 13 amino acid residues respective in the Kringle 5 and α-chain of C3b directly implicated in the binding and the main stabilizing forces were electrostatic force (-55.99 ± 11.82 kcal/mol) and Van der Waals forces (-42.70 ± 3.45 kcal/mol). Additionally, a loop structure (65-71) in Kringle 5 underwent a conformational change from a random structure to an α-helix and a loop structure (417-425) in α-chain of C3b was closer to the molecular center, both of them were more conducive to the binding between them. Meanwhile, the involvement of the lysine binding site of Kringle 5 played an important role in the binding process. In addition, the erythrocyte-antibody complement rosette assay substantiated that the presence of Kringle 5 hindered the transportation of α-chain of C3b to antigen-antibody complex in a dose-dependent manner. These findings collectively indicated that the α-chain of C3b is very likely a receptor protein for Kringle 5, which provides a methodology for other similar investigations and valuable insights into expansion of the pharmacological effects and potential application of Kringle 5 in immune-related diseases.

A novel tryptanthrin-based "on-off-on" probe for sequential sensing Cu2+/S2- in water samples.

Copper ions (Cu2+) and sulfide (S2-) play essential roles in many physiologies and pathologic processes. Herein, a new "on-off-on" tryptanthrin-based probe TR-1 (TR-1) has been designed and synthesized in a facile and economical way. TR-1 exhibited highly selective and sensitive response to Cu2+ without any interference over 14 competitive metal ions and the detection limit downs to 24 nM, which is far below the Chinese standard of fishery water quality (157 nM). The 'in situ' prepared complex TR-1 + Cu2+ could also be applied to detect S2- with the detection limit of 62 nM. Further, TR-1 was potentially applied for the analysis of copper ions in water samples.

"Cognitive" Criteria in Older Adults With Slow Gait Speed: Implications for Motoric Cognitive Risk Syndrome.

BACKGROUND: Motoric cognitive risk syndrome (MCR) is a predementia condition that combines slow gait speed and subjective cognitive concerns (SCC). The SCC criterion is presently unstandardized, possibly limiting risk detection. We sought to (a) characterize SCC practices through MCR literature review; (b) investigate the ability of SCC in slow gait individuals in predicting the likelihood of cognitive impairment in a demographically diverse sample of community-dwelling, nondemented older adults. METHODS: First, we comprehensively reviewed the MCR literature, extracting information regarding SCC measures, items, sources, and cognitive domain. Next, Einstein Aging Study (EAS) participants (N = 278, Mage = 77.22 ±â€…4.74, %female = 67, Meducation = 15 ±â€…3.61, %non-Hispanic White = 46.3) completed gait, Clinical Dementia Rating Scale (CDR), and SCC assessment at baseline and annual follow-up (Mfollow-up = 3.5). Forty-two participants met slow gait criteria at baseline. Generalized linear mixed-effects models examined baseline SCC to predict cognitive impairment on CDR over follow-up. RESULTS: We reviewed all published MCR studies (N = 106) and documented ambiguity in SCC criteria, with a prevalent approach being use of a single self-reported memory item. In EAS, high SCC endorsement on a comprehensive, validated screen significantly affected the rate of cognitive impairment (CDR; ßinteraction = 0.039, p = .018) in slow gait individuals. CONCLUSIONS: An assessment approach that queries across numerous SCC domains was found to predict future decline in clinical dementia status in slow gait older adults. Current SCC practices in MCR, which tend to utilize a single-memory item, may not be the optimal approach. We discuss the implications of SCC criteria validation and standardization to enhance early dementia detection in MCR.

Does the Cognitive Change Index Predict Future Cognitive and Clinical Decline? Longitudinal Analysis in a Demographically Diverse Cohort.

Background: The Cognitive Change Index (CCI) is a widely-used measure of self-perceived cognitive ability and change. Unfortunately, it is unclear if the CCI predicts future cognitive and clinical decline. Objective: We evaluated baseline CCI to predict transition from normal cognition to cognitive impairment in nondemented older adults and in predementia groups including, subjective cognitive decline, motoric cognitive risk syndrome, and mild cognitive impairment. Different versions of the CCI were assessed to uncover any differential risk sensitivity. We also examined the effect of ethnicity/race on CCI. Methods: Einstein Aging Study participants (N = 322, Mage = 77.57±4.96, % female=67.1, Meducation = 15.06±3.54, % non-Hispanic white = 46.3) completed an expanded 40-item CCI version (CCI-40) and neuropsychological evaluation (including Clinical Dementia Rating Scale [CDR], Montreal Cognitive Assessment, and Craft Story) at baseline and annual follow-up (Mfollow - up=3.4 years). CCI-40 includes the original 20 items (CCI-20) and the first 12 memory items (CCI-12). Linear mixed effects models (LME) and generalized LME assessed the association of CCI total scores at baseline with rate of decline in neuropsychological tests and CDR. Results: In the overall sample and across predementia groups, the CCI was associated with rate of change in log odds on CDR, with higher CCI at baseline predicting faster increase in the odds of being impaired on CDR. The predictive validity of the CCI broadly held across versions (CCI-12, 20, 40) and ethnic/racial groups (non-Hispanic black and white). Conclusions: Self-perception of cognitive change on the CCI is a useful marker of dementia risk in demographically/clinically diverse nondemented samples. All CCI versions successfully predicted decline.

Non-literacy biased, culturally fair cognitive detection tool in primary care patients with cognitive concerns: a randomized controlled trial.

Dementia is often undiagnosed in primary care, and even when diagnosed, untreated. The 5-Cog paradigm, a brief, culturally adept, cognitive detection tool paired with a clinical decision support may reduce barriers to improving dementia diagnosis and care. We performed a randomized controlled trial in primary care patients experiencing health disparities (racial/ethnic minorities and socioeconomically disadvantaged). Older adults with cognitive concerns were assigned in a 1:1 ratio to the 5-Cog paradigm or control. Primary outcome was improved dementia care actions defined as any of the following endpoints within 90 days: new mild cognitive impairment syndrome or dementia diagnoses as well as investigations, medications or specialist referrals ordered for cognitive indications. Groups were compared using intention-to-treat principles with multivariable logistic regression. Overall, 1,201 patients (mean age 72.8 years, 72% women and 94% Black, Hispanic or Latino) were enrolled and 599 were assigned to 5-Cog and 602 to the control. The 5-Cog paradigm demonstrated threefold odds of improvement in dementia care actions over control (odds ratio 3.43, 95% confidence interval 2.32-5.07). No serious intervention-related adverse events were reported. The 5-Cog paradigm improved diagnosis and management in patients with cognitive concerns and provides evidence to promote practice change to improve dementia care actions in primary care.ClinicalTrials.gov: NCT03816644 .

NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors.

To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10-9) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy.

Physiological mechanism of sodium salicylate and folcisteine on alleviating salt stress in wheat seedlings.

Soil salinization substantially hampers the growth and development of wheat, potentially leading to plant death in severe cases, thus reducing grain yield and quality. This phenomenon poses a significant threat to food security in China. We investigated the effects of two exogenous plant growth regulators, sodium salicylate and folcisteine, on the wheat physiology and key characteristics under salt stress using hydroponics method. The results indicated that both regulators effectively mitigated the growth inhibition of wheat under salt stress. We assessed morphological and physiological indexes, including antioxidant enzyme activities (superoxide dismutase [SOD], catalase [CAT], peroxidase [POD]) and malondialdehyde (MDA) concentration in wheat after foliar application of sodium salicylate and folcisteine under salt stress. The findings revealed that sodium salicylate was more effective than folcisteine. However, folcisteine showed superior performance in reducing hydrogen peroxide (H2O2) content and superoxide anion (O2-) level compared to sodium salicylate. Simultaneously, Concurrent application of both regulators synergistically enhanced their efficacy, yielding the most favorable outcomes. In addition, this study noted that while the initial effects of these regulators were not pronounced, their sustained application significantly improved wheat growth in stressful condition and alleviated the detrimental impacts of salt stress. This approach could effectively guarantee the food security and production in China.

Trans-retro-peritoneal laparoscopic partial nephrectomy for posterior hilar tumor: technical feasibility and preliminary results.

Background: Urologists still encounter challenges when it comes to the surgical management of tumors located on the posterior lip and posterior renal hilar region. We propose a trans-retro-peritoneal (TRP) technique to address the difficulties associated with posterior hilar tumors during retroperitoneal laparoscopic partial nephrectomy (LPN). Its efficacy was evaluated in a retrospective case-control study. Methods: The patients with posterior hilar tumors (≤7 cm) that underwent retroperitoneal LPN were included. The TRP technique allowed the posterior hilar tumor completely visible by incising the ventral peritoneum and rotating kidney ventrally during retroperitoneal LPN, which was applied in 36 cases, while the conventional retroperitoneal LPN was performed in 22 cases. Perioperative data were analyzed to evaluate the efficacy of TRP-LPN. Results: In TRP-LPN group, the TRP technique was successfully performed in all the patients without converting to open surgery or radical nephrectomy. The warm ischemia time was significantly shorter in TRP-LPN group than conventional LPN group (20.3 vs. 28.5 min, P<0.001). Furthermore, the mean estimated blood loss in TRR-LPN group was significantly less than that in conventional LPN group (86.5 vs. 90.9 mL, P<0.05). The mean operation time and recovery time of gastrointestinal function were similar between two groups. No severe complications occurred, and no positive surgical margin was found. The rate of Trifecta achievement was 50.0% (18/36) and 31.8% (7/22) respectively for TRP-LPN and conventional LPN (P=0.175). After mean follow-up of 21 months, no recurrence or metastasis occurred in all cases. Conclusions: Our findings, as demonstrated by the Trifecta outcomes, support the feasibility and efficacy of TRP-LPN in managing posterior renal hilar tumors. This approach may be considered as an efficient option for surgical management of such tumors.