Search

Ethnopharmacological Relevance: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, mainly manifested as paresthesia. Tangzu granule (TZG) is derived from famous traditional Chinese medicine decoctions and optimized by long-term temporary practice. TZG has good efficacy in improving numbness, pain and pruritus of the lower extremities of DPN patients. However, the overall regulatory mechanisms underlying its effects on DPN remain unclear., Aim of the Study: This study aims to explore the potential mechanism of TZG for treating DPN., Materials and Methods: Sprague-Dawley (SD) rats were used to establish an in vivo model of DPN with streptozotocin (STZ) injection and high-fat diet (HFD) feeding. Additionally, sciatic glial RSC96 cells were induced with high glucose in vitro. SD rats in intervention group received TZG treatment for 12 weeks. After 12 weeks of treatment, sciatic nerve function was evaluated by intelligent hot plate meter and neuro electrophysiology detector. The morphological changes of sciatic nerve cells were observed by hematoxylin-eosin staining and transmission electron microscope. IL-1β, IL-18 inflammatory cytokines, pyroptosis and P2X7R/NLRP3 signaling pathway were observed by Western blotting, immunofluorescence staining and ELISA., Results: TZG improved nerve conduction velocity and sciatic neuropathy rational structural changes in DPN rats. It also inhibited RSC96 inflammatory response and cell death that induced by high glucose. This may be related to TZG inhibiting P2X7R, decreasing the activation of NLRP3 inflammasomes, down-regulating the levels of pyroptosis proteins such as caspase-1, cleaved caspase-1, gasdermin D (GSDMD), and GSDMD-N, and inhibiting the release of interleuki (IL)-18 and IL-1β inflammatory cytokines., Conclusions: TZG inhibited pyroptosis through P2X7R/NLRP3 signaling pathway, alleviated neuroinflammation, and showed protective effect in the treatment of DPN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The combined treatment with histone deacetylase (HDAC) inhibitors with peroxisome proliferator-activated receptor γ (PPARγ) agonists has displayed significant anticancer efficacy. Based on these results, a series of cloxiquine derivatives were prepared as potent HDAC inhibitors for the treatment of melanoma. Among these compounds, CS4 exhibited excellent inhibitory effects on HDAC1 (IC 50  = 38 nM) and HDAC6 (IC 50  = 12 nM), and had good antiproliferative effects against A375 and SK-MEL-5 melanoma cells (IC 50 values, 1.20 and 0.93 μM, respectively). Mechanism research indicated that CS4 inhibited SK-MEL-5 cell growth by promoting α-tubulin and histone 3 (H3) acetylation. At the metabolic level, treatment with BG11 activated PPARγ and blocked glycolysis in SK-MEL-5 cells, which mediated partial antimelanoma effects of CS4. In addition, CS4 also induced cell cycle arrest at G2, suppressed migration and facilitated apoptosis of SK-MEL-5 cells. More importantly, compound CS4 demonstrated significant in vivo anticancer effect compared with SAHA, and exhibited neglectable toxicity. Consequently, CS4 is the potent HDAC inhibitor, which may be developed as the candidate antimelanoma drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Chronic respiratory diseases (CRDs) have been shown to be associated with frailty, but these findings have not yet reached a consensus. The aim of this study was to investigate the association between CRDs and frailty in the elderly using a nationally representative data from China., Methods: Data from the China Health and Retirement Longitudinal Study (CHARLS) were analysed, including 3309 frailty-free participants followed for three waves from 2011. Frailty was assessed using the physical frailty phenotype scale, and CRDs were conformed by self-reported physician diagnoses. Cox proportional hazard models were used to examine the association between baseline CRDs and subsequent frailty., Results: Among participants (mean age 67.07 years, 51.53% male), 497 (15.02%) had CRDs. During a mean follow-up of 46 months, 273 (8.25%) participants developed frailty. The incidence rate of frailty was significantly higher in the CRDs group (37.17% per 1000 person-years vs 18.41% per 1000 person-years, p<0.01). Adjusted for covariables, participants with CRDs had a 44% higher risk of developing frailty (HR = 1.44, 95% CI: 1.08 to 1.91). Specifically, asthma only (HR=1.89, 95% CI: 1.07 to 3.33) and asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) (HR=1.79, 95% CI: 1.19 to 2.69) were associated with a higher risk of frailty among the elderly, while COPD only was not (HR=1.11, 95% CI: 0.73 to 1.65)., Conclusion: This study shows a significant association between CRDs, particularly asthma only and ACO, and frailty in the elderly. We need to pay attention to the frailty status of CRDs patients and consider routine screening among them in both clinical practice and community settings. Active treatment and control of CRDs are necessary to avoid frailty caused by primary lung disease progression or exacerbation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Despite remarkable advancements in the organic synthesis field facilitated by the use of machine learning (ML) techniques, the prediction of reaction outcomes, including yield estimation, catalyst optimization, and mechanism identification, continues to pose a significant challenge. This challenge arises primarily from the lack of appropriate descriptors capable of retaining crucial molecular information for accurate prediction while also ensuring computational efficiency. This study presents a successful application of ML for predicting the performance of Ir-catalyzed allylic substitution reactions. We introduce SubA, an innovative substrate-aware descriptor that is inspired by the fact that specific atoms or motifs in reactants drive the reaction outcomes. By employing graph matching algorithms for molecular backbone identification and incorporating atomic and molecular properties derived from density functional theory calculations, SubA extracts essential information at both the atomic level and the molecular level. Compared to four mainstream descriptors, SubA achieves reduced dimensionality and enhanced prediction accuracy with over 2% mean absolute error reduction in both random and scaffold splitting evaluations. It also demonstrates better generalization when confronted with previously unreported substrate combinations in extended experiments. Furthermore, an interpretable analysis of SubA shows that the predictor focuses on key molecular and atomic features, offering insights into reaction mechanisms.

Background: This study investigates the association between the neutrophil-percentage-to-albumin ratio (NPAR) and all-cause mortality in patients with hypertension, and its relationship with cardiovascular mortality., Methods: This study examined data from 18,469 adults with hypertension in the National Health and Nutrition Examination Survey (1999-2018) and the mortality data from the National Death Index. The link between NPAR and mortality risk was visualized using restricted cubic splines. The optimal NPAR cut-off value for the prediction of survival outcomes was identified via maximally selected rank statistics. We employed weighted multivariate Cox regression and subgroup analyses to evaluate the relationship between NPAR and risk of all-cause and cardiovascular mortality. We assessed NPAR's predictive accuracy for survival outcomes using time-related receiver operating characteristic analysis., Results: During a median follow-up of 105 months, 31.8 % of 18,469 participants died, with 8.9 % from cardiovascular causes. Restricted cubic splines analysis showed a positive link between NPAR and both all-cause and cardiovascular mortality. Cox models indicated that higher NPAR (>1602.08) significantly raised risks of all-cause (HR 1.80, 95 % CI 1.54-2.12, p < 0.0001) and cardiovascular mortality (HR 1.54, 95 % CI 1.24-1.91, p < 0.0001). The stability of results was confirmed through stratified and interaction analyses. The area under the curve for 3-, 5-, and 10-year survival were 0.67, 0.65, and 0.63 for all-cause mortality and 0.61, 0.62, and 0.63 for cardiovascular mortality., Conclusions: Elevated NPAR independently raises the risk of all-cause and cardiovascular mortality in hypertensive patients, indicating its potential in the clinic as a practical tool for predicting long-term mortality risks and influencing treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study investigated the effects of waxy (Wx) protein on wheat V-type resistant starch (RS 5 ) formation, molecular structure, and physicochemical properties. We discovered that waxy protein deletions led to a rise in B- and C-type starch granules, while reducing A-type starch granules, amylose, and slowly digestible starch contents. Further, dodecyl gallate (DG) addition significantly increased RS 5 content, and molecular dynamics simulations indicated that amylose and DG can form stable complexes. Molecular docking indicated that DG could potentially aid in protecting wheat starch from digestion by human α-glucosidase. RS 5 content was significantly reduced by waxy protein deletions. X-ray powder diffraction, Fourier-transform infrared spectroscopy, and laser confocal microscopy-Raman analyses revealed that waxy protein deletions decreased long-range crystalline structures and relative crystallinity and increased short-range crystalline structures，and full width at half maximum at 480 cm -1 of RS 5 . Pearson correlation analysis showed that RS 5 content was highly correlated with its crystal structure, functional characteristics, and digestive characteristics. Principal component analysis revealed that five parameters (amylopectin, long-range crystalline structures, amylose, relative crystallinity, and RS 5 content) had significant effect on the crystalline structure and functionality of RS 5 ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Different from salt, metal chelate is a novel state of drug constructed by more separate coordinate bonds to form a chelating circle. Due to their composition similarity, it is hard to distinguish them except identifying ionic bond (i.e., salt) or coordinate bond (i.e., chelate) in the single crystal structure. In this study, sodium chelate (CDCC No: 1865670) and lithium salt (CDCC No: 2161617) of puerarin (PUE) was prepared. In addition to difference in single crystal structure, it was found that they showed totally different phase solubility behaviors: lithium salt demonstrated a typical inverse proportion curve as other common salts, while sodium chelate exhibited disordered scatters. However, when incorporating the unit PUE-Na complex in solution state and complexation constant K 11 in chemical equation, the scatters in phase solubility diagram of chelate could be well fitted and the value of K 11 was dramatically higher with orders of magnitude than the dissociation constant K c ; while processing phase solubility curve of lithium salt by incorporating complex item, it could not well match the curve at all. PUE sodium chelate is more likely to be a weak electrolyte with partial dissociation, while PUE lithium salt acted as a strong electrolyte with complete dissociation. The phase solubility test would be served as a surrogate tool for differentiation of chelates from salts when single crystal was not available., Competing Interests: Declaration of competing interest The authors declare no competing financial interest. All authors have approved the manuscript and agree with its submission to Journal of Pharmaceutical Sciences. We confirm that this manuscript has not been previously published in any language anywhere and that it is not under simultaneous consideration by another journal., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)