Curcuma wenyujin rhizomes extract ameliorates lipid accumulation.

Curcuma wenyujin (C. wenyujin) is a medicinal plant that is traditionally used to treat blood stagnation, liver fibrosis, pain, and jaundice. In this study, we examined the effect of C. wenyujin rhizome extract on hepatic lipid accumulation both in vivo and in vitro. We found that the petroleum ether fraction of C. wenyujin rhizome extract (CWP) considerably reduced the accumulation of lipids in HepG2 cells treated with oleic and palmitic acid. Ultra-high-performance liquid chromatography coupled with LTQ-Orbitrap mass spectrometry was used to analyze the main chemical constituents of CWP, and 21 sesquiterpenes were identified. In vivo experiments revealed that the administration of CWP significantly reduced the body weight and serum total cholesterol (TC) level of low-density-lipoprotein receptor knockout mice treated with a high-fat diet without affecting their food intake. CWP also significantly reduced the levels of liver TC, liver triglycerides, aspartate transaminase, and alanine transaminase. Histological examination revealed that CWP dose-dependently reduced steatosis in liver tissue, significantly downregulated the expression of lipogenesis genes, and increased the ß-oxidation of fatty acids. CWP also significantly increased autophagy-related proteins. In conclusion, CWP rich in sesquiterpenes reduces the accumulation of lipids in vivo and in vitro by improving lipid metabolism and activating autophagy.

Study on risk factors and receiver operator characteristic curve of iatrogenic withdrawal syndrome in pediatric intensive care units ---A retrospective study.

OBJECTIVE: To investigate the independent risk factors associated with iatrogenic withdrawal syndrome in pediatric intensive care units (PICUs) and to establish receiver operator characteristic (ROC) curve to facilitate the diagnosis of iatrogenic withdrawal syndrome in clinical settings. METHOD: Pediatric patients who received analgesic and sedative medication at a tertiary hospital in the southern Zhejiang region of China between January 2016 and December 2022 were selected for the study. Clinical case data were retrospectively analyzed to gather information including age, gender, weight, total dose of analgesic and sedative medication, total treatment duration, average maintenance dose, and other relevant parameters. Medically-induced withdrawal symptom scores were assessed using the Sophia Observation Scale for Withdrawal Symptoms (SOS). Univariate and multivariate logistic regression analyses were conducted on the above indicators to identify the risk factors for iatrogenic withdrawal, and an ROC curve was constructed. RESULTS: The study encompassed a total of 104 pediatric patients, comprising 47 patients in the SOS score ≥ 4 group and 57 patients in the SOS score ≤ 3 group. The incidence of iatrogenic withdrawal was 45.19%. Univariate analysis identified cumulative total dose of fentanyl, average daily dose of fentanyl, average daily dose of midazolam, and patient weight (p<0.05) as factors associated with iatrogenic withdrawal syndrome. The logistic multiple regression analysis revealed that the average daily dose of fentanyl was an independent risk factor for the occurrence of iatrogenic withdrawal syndrome in critically ill children (p<0.05). ROC curve analysis indicated an area under the curve of 0.711 (95% CI: 0.610-0.811) with sensitivity and specificity of 73.7% and 61.7%, respectively. CONCLUSION: The average daily maintenance dose of fentanyl holds significant clinical value in diagnosing and evaluating the prognosis of iatrogenic withdrawal syndrome, and can provide a scientific foundation for enhancing sedative and analgesic management in clinical practice.

Optimization of Bilayer Resistive Random Access Memory Based on Ti/HfO2/ZrO2/Pt.

In this paper, the electrothermal coupling model of metal oxide resistive random access memory (RRAM) is analyzed by using a 2D axisymmetrical structure in COMSOL Multiphysics simulation software. The RRAM structure is a Ti/HfO2/ZrO2/Pt bilayer structure, and the SET and RESET processes of Ti/HfO2/ZrO2/Pt are verified and analyzed. It is found that the width and thickness of CF1 (the conductive filament of the HfO2 layer), CF2 (the conductive filament of the ZrO2 layer), and resistive dielectric layers affect the electrical performance of the device. Under the condition of the width ratio of conductive filament to transition layer (6:14) and the thickness ratio of HfO2 to ZrO2 (7.5:7.5), Ti/HfO2/ZrO2/Pt has stable high and low resistance states. On this basis, the comparison of three commonly used RRAM metal top electrode materials (Ti, Pt, and Al) shows that the resistance switching ratio of the Ti electrode is the highest at about 11.67. Finally, combining the optimal conductive filament size and the optimal top electrode material, the I-V hysteresis loop was obtained, and the switching ratio Roff/Ron = 10.46 was calculated. Therefore, in this paper, a perfect RRAM model is established, the resistance mechanism is explained and analyzed, and the optimal geometrical size and electrode material for the hysteresis characteristics of the Ti/HfO2/ZrO2/Pt structure are found.

Effects of polyphenol and gelatin types on the physicochemical properties and emulsion stabilization of polyphenol-crosslinked gelatin conjugates.

Herein, six types of polyphenol-crosslinked gelatin conjugates (PGCs) with ≥ two gelatin molecules were prepared using a covalent crosslinking method with two types of polyphenols (tannic acid and caffeic acid) and three types of gelatins (bovine bone gelatin, cold water fish skin gelatin, and porcine skin gelatin) for the emulsion stabilization. The structural and functional properties of the PGCs were dependent on both polyphenol and gelatin types. The storage stability of the conjugate-stabilized emulsions was dependent on the polyphenol crosslinking, NaCl addition, and heating pretreatment. In particular, NaCl addition promoted the liquid-gel transition of the emulsions: 0.2 mol/L > 0.1 mol/L > 0.0 mol/L. Moreover, NaCl addition also increased the creaming stability of the emulsions stabilized by PGCs except tannic acid-crosslinked bovine bone gelatin conjugate. All the results provided useful knowledge on the effects of molecular modification and physical processing on the properties of gelatins.

[Study on allergen components of birch pollen in Beijing area].

Objective:To explore the allergen components of birch pollen in the Beijing area and interpret its clinical significance. Methods:A total of 58 patients with birch pollen allergy were included in the cross-sectional study and divided into allergic rhinitis（AR） and allergic asthma（AA） groups according to clinical manifestations. Concentration of birch pollen allergen sIgE, as well as Bet v 1, Bet v 2, Bet v 4 and Bet v 6 sIgE were detected by ImmunoCAP immunolinked immunoassay. Differences of sIgE concentration of birch pollen allergen component in AR and AA were analyzed. Results:There were 44（75.9%） cases of AR and 14（24.1%） cases of AA were enrolled. All the 18 patients with spring pollen allergy were AR patients without AA. There were 40 cases with both spring and autumn pollen allergy, of which 26 cases（65%） were AR and 14 cases（35%） were AA. The sIgE of birch pollen allergen was level 2 or above in all subjects. 94.8% were positive for any four allergen components. 77.6% were mono-sensitized to any allergen component while 17.2% were dual-sensitized. The positive rate of Bet v 1 and/or Bet v 2 was 93.1%. The positive rates of four protein components were: Bet v 1（82.8%）, Bet v 2（29.3%）, Bet v 6（1.7%）, Bet v 4（0%）. sIgE of birch pollen was positively correlated with sIgE level of Betv 1（r=0.898, P<0.001）. The sIgE concentration of Bet v2 in AA group was significantly higher than that in AR group（[4.34±14.35] kUA/L vs [1.56±3.26] kUA/L, P<0.05）. There was no significant difference in other components. Conclusion:Bet v 1 is the main allergen component of birch pollen in the Beijing area, and Bet v 1 plus Bet v 2 can diagnose more than 90% of birch pollen allergy.

Exploring charge generation and separation in tandem organic light-emitting diodes based on magneto-electroluminescence.

5,6,11,12-tetraphenylnaphthacene (rubrene) exhibits resonant energy properties (ES1,rub≈ 2ET1,rub), resulting in rubrene-based organic light-emitting diode (OLED) devices that undergo the singlet fission (STT) process at room temperature. This unique process gives rise to a distinct magneto-electroluminescence (MEL) profile, differing significantly from the typical intersystem crossing (ISC) process. Therefore, in this paper, we investigate charge generation and separation in the interconnector, and the mechanism of charge transport in tandem OLEDs at room temperature using MEL tools. We fabricate tandem OLEDs comprising green (Alq3) and yellow (Alq3:rubrene) electroluminescence (EL) units using different interconnectors. The results demonstrate that all devices exhibited significant rubrene emission. However, the MEL did not exhibit an STT process with an increasing magnetic field, but rather a triplet-triplet annihilation (TTA) process. This occurrence is attributed to direct carrier trapping within doped EL units, which hinders the transport of rubrene trapped charges, consequently prolonging the lifetime of triplet excitons (T1,rub). Thus, the increased T1,rubconcentration causes TTA to occur at room temperature, causing the rapid decrease of MEL in all devices under high magnetic fields. In devices where only the TTA process occurs, the TTA increases with the increasing current. Consequently, the high magnetic field of devices A-C is only related to TTA. Notably, there exists a high magnetic field TTA of device D in the Alq3/1,4,5,8,9,11-Hexaazatriphenylene-hexacarbonitrile interconnector regardless of the current. This occurs because both EL units in the device emit simultaneously, resulting in the triplet-charge annihilation process of Alq3in the high magnetic field of the MEL. Moreover, the rapid increase in MEL at low magnetic field across all devices is attributed to the ISC between Alq3polaron pairs. This entire process involves Förster and Dexter energy transfer. This article not only provides novel insights into charge generation and separation in the interconnector but also enhances our understanding of the microscopic mechanisms in tandem OLED devices.

Achieving High Performance of ZnSnO Thin-Film Transistor via Homojunction Strategy.

The zinc-tin-oxide (ZTO) thin-film transistor (TFT) is one of the most promising candidates for advanced display applications, though its popularity is limited by its performances. In this work, a heterojunction channel strategy was adopted to regulate the electron transport behaviors and the TFT performances by manipulating the concentration and the distribution of oxygen vacancies, and a reasonable physical model was proposed based on experimental and simulation results. It is difficult to mediate the contradiction between mobility and threshold voltage for the single channel. Via a heterojunction channel strategy, desirable TFT performances, with mobility of 12.5 cm2/Vs, threshold voltage of 1.2 V and Ion/Ioff of 3 × 109, are achieved when the oxygen-vacancy-enriched layer gets close to the gate insulator (GI). The enhanced performances can be mainly attributed to the formation of two-dimensional electron gas (2DEG), the insensitive potential barrier and the reasonable distribution of oxygen vacancy. On the contrary, when the oxygen-vacancy-enriched layer stays away from GI, all the main performances degenerate due to the vulnerable potential well. The findings may facilitate the development and application of heterojunction channels for improving the performances of electronic devices.

Profiles of Birch Allergen Component Sensitization and Its Association with Pollen Food Allergy Syndrome in Northern China.

Purpose: To investigate the major allergen components associated with birch pollen allergy in northern China and elucidate clinical relevance to pollen food allergy syndrome (PFAS). Methods: Fifty-eight patients were recruited for a cross-sectional study and categorized into two groups: PFAS group and non-PFAS group, as well as apple allergy group and non-apple allergy group. The sIgE levels of birch pollen and its components, namely Bet v 1, Bet v 2, Bet v 4, and Bet v 6, were analyzed. Results: Among 58 participants, 44 individuals (75.9%) reported PFAS. 32 out of 44 (72.7%) participants reported apple allergy. Bet v 1 exhibited the highest sensitization rate at 82.8%, followed by Bet v 2 (29.3%) and Bet v 6 (1.7%). The combined sensitization rate for Bet v 1 and/or Bet v 2 was 93.1%. A total of 77.6% of the subjects demonstrated sensitization to single component, while 19.0% exhibited sensitization to two components. The sIgE levels of birch pollen and Bet v 1 were significantly elevated in PFAS group compared to non-PFAS group (p=0.001, p<0.001, respectively), as well as in apple-allergic and non-apple-allergic group (p<0.001, p<0.001, respectively). The optimal cut-off values for birch pollen and Bet v 1 sIgE were determined to be 7.09 kUA/L (with a sensitivity of 84.1% and specificity of 78.6%) and 5.11 kUA/L (with a sensitivity of 75.0% and specificity of 85.7%) when diagnosing PFAS. In terms of apple allergy, the optimal cut-off value were 9.40 kUA/L (with a sensitivity of 81.3% and specificity of 76.9%) and 6.53 kUA/L (with a sensitivity of 84.4% and specificity of 84.6%), respectively. Conclusion: The predominant sensitization pattern is mono-sensitization to Bet v 1, but when considering immunotherapy, Bet v 2 should also be taken into account. Bet v 1 serves as a valuable biomarker for diagnosing PFAS and apple allergy.

Tetrazole and acylsulfonamide bioisosteric replacements of the carboxylic acid in a dual MCL-1/BCL-xL inhibitor are tolerated.

Overexpression of the anti-apoptotic protein MCL-1 is associated with a plethora of human cancers, and it reduces the sensitivity of cancer cells to approved chemotherapies. Accordingly, the discovery of MCL-1 inhibitors is an active area of interest. Many inhibitors of the anti-apoptotic MCL-1 protein bear a crucial carboxylic acid that may engage Arg263 in the BH3-binding groove. We previously described the salicylic acid-based dual MCL-1/BCL-xL inhibitor 17cd, which is currently undergoing lead optimization. As part of that process, we wished to investigate bioisosteric replacement of 17cd's key carboxylic acid. Herein we describe the synthesis of a variety of analogues of a simpler analogue of 17cd presenting carboxylic acid surrogates. The acylsulfonamide and tetrazole motifs, which exhibit comparable pKas to the carboxylic acid function, displayed similar, or better, binding affinities to MCL-1 and BCL-xL as the corresponding carboxylic acid-containing lead. Our best compound was acylsulfonamide 7d with a Ki of 800 nM against MCL-1 and 1.82 mM against BCL-xL, and demonstrated an improved effect on the viability of the HL60 acute myeloid leukemia cell line relative to the parent carboxylic acid-containing dual inhibitor from which it was derived.

YAP/ACSL4 Pathway-Mediated Ferroptosis Promotes Renal Fibrosis in the Presence of Kidney Stones.

The potential association between calcium oxalate stones and renal fibrosis has been extensively investigated; however, the underlying mechanisms remain unclear. Ferroptosis is a novel form of cell death characterized by iron-dependent lipid peroxidation and regulated by acyl coenzyme A synthase long-chain family member 4 (ACSL4). Yes-associated protein (YAP), a transcriptional co-activator in the Hippo pathway, promotes ferroptosis by modulating ACSL4 expression. Nevertheless, the involvement of YAP-ACSL4 axis-mediated ferroptosis in calcium oxalate crystal deposition-induced renal fibrosis and its molecular mechanisms have not been elucidated. In this study, we investigated ACSL4 expression and ferroptosis activation in the kidney tissues of patients with calcium oxalate stones and in mice using single-cell sequencing, transcriptome RNA sequencing, immunohistochemical analysis, and Western blot analysis. In vivo and in vitro experiments demonstrated that inhibiting ferroptosis or ACSL4 mitigated calcium oxalate crystal-induced renal fibrosis. Furthermore, YAP expression was elevated in the kidney tissues of patients with calcium oxalate stones and in calcium oxalate crystal-stimulated human renal tubular epithelial cell lines. Mechanistically, in calcium oxalate crystal-stimulated human renal tubular epithelial cell lines, activated YAP translocated to the nucleus and enhanced ACSL4 expression, consequently inducing cellular ferroptosis. Moreover, YAP silencing suppressed ferroptosis by downregulating ACSL4 expression, thereby attenuating calcium oxalate crystal-induced renal fibrosis. Conclusively, our findings suggest that YAP-ACSL4-mediated ferroptosis represents an important mechanism underlying the induction of renal fibrosis by calcium oxalate crystal deposition. Targeting the YAP-ACSL4 axis and ferroptosis may therefore hold promise as a potential therapeutic approach for preventing renal fibrosis in patients with kidney stones.

Realizing high efficiency and luminance in green, yellow and blue organic light emitting diode by deoxyribonucleic acid.

Although the effect of the electron blocking layer (EBL) material, deoxyribonucleic acid (DNA), on the electroluminescence (EL) performance of organic light-emitting diodes (OLEDs) has been studied, the process of DNA regulation of exciton recombination region within the device is still unclear. Herein, devices with and without EBL were fabricated using different DNA spin-coating speeds, and the photoelectric performance of device were measured. By using DNA compounded with cetyltrimethyl ammonium (CTMA) as the EBL and hole buffer layer, so-called BioLEDs. The DNA-based green Alq3BioLEDs achieve higher luminance (39 000 cd m-2) and higher current efficiency (8.4 cd A-1), which are increased by 49% and 54%, respectively, compared to the reference OLEDs without the addition of DNA. Similarly, the maximum luminance and efficiency of yellow Rubrene BioLEDs is increased by 64% (from 12 120 to 19 820 cd m-2) and 74% (from 1.36 to 2.36 cd A-1), the luminance and efficiency of blue TCTA BioLEDs is increased by 101% and 245%. Specifically, we found that as the thickness of DNA-CTMA increases, the exciton recombination region moves towards the interface between the emitting layer (EML) and the hole transport layer (HTL). By better confining excitons within the EML, the current efficiency of the BioLEDs is effectively improved. Accordingly, we provide a possible idea for achieve high performance DNA-based BioLEDs by adding DNA-CTMA EBL and hole buffer layers. Meanwhile, as the DNA thickness increases, the exciton recombination region moves towards the EML/HTL interface, thereby enhancing the efficiency of the DNA-based BioLEDs.

Potassium stearate doped PEDOT:PSS improves the performance of inverted perovskite solar cells.

Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) suffers from lower conductivity and surface defects, which hinders the extraction and transport of effective charges, thereby reducing the Power conversion efficiency (PCE) and long-term stability of PSCs. Therefore, this study introduces potassium stearate (KSt) doping in PEDOT:PSS to regulate its conductivity and interface charge transfer. As a result, KSt-doped PEDOT:PSS increase the PCE of the device from 16.35% to 18.35%. Moreover, the PCE of PSCs with KSt-doped PEDOT:PSS can maintain 87% of its initial value after being stored in a glove box for over 700 hours. This work provides a simple and effective method for designing high-performance and stable PSCs.

Mediation of exciton concentration on magnetic field effects in NPB : Alq3-based heterojunction OLEDs.

Organic light-emitting diodes (OLEDs) are considered one of the most promising new display technologies owing to their advantages, such as all-solid-state, high color gamut, and wide viewing angle. However, in terms of special fields, the brightness, lifetime, and stability of the devices need further improvement. Therefore, heterojunction devices with different concentrations were prepared to regulate device brightness. The brightness of the bulk heterojunction device is enhanced by 9740 cd m-2, with a growth rate of about 26.8%. The impact of various temperatures and various exciton concentrations on the device magneto-conductance (MC) and magneto-electroluminescence (MEL) was investigated. Experimental results demonstrate that the exciton concentration inside the device can be tuned to improve optoelectronic properties and organic magnetic effects. The complex spin mixing process inside the bulk heterojunction device is deeply investigated, which provides a reliable basis for the design of bulk heterojunction devices.

Investigations on exciton recombination and annihilation in TmPyPB-ETL OLEDs using magnetic field effects.

Although the effect of the electron transport layer (ETL) material TmPyPb on the electroluminescence performance of organic light-emitting diodes (OLEDs) has been extensively studied, the process of TmPyPb regulating exciton recombination and annihilation within the device is still unclear. Here, we fabricated devices of various TmPyPb thicknesses with and without ETL. Subsequently, we measured the magneto-electroluminescence (MEL) of these devices. Specifically, at the same luminance, the triplet-charge annihilation (TQA) process is more likely to occur as the thickness of TmPyPb increases, resulting in a decrease in the maximum luminance of devices. Due to electron leakage and exciton recombination region moving towards the cathode, leading to a decrease in luminance efficiency at first and then an enhancement with an increase in the thickness of TmPyPb. Furthermore, at room temperature, the application of a large bias voltage suppresses singlet fission (SF) processes by modulating the dissociation of singlet polaron pairs (PPS) and the concentration of triplet exciton (T1). This leads to the conversion of SF to the TQA process. At low temperatures, the bias voltage and temperature can regulate the concentration and lifetime of PPS and T1. Therefore, as the temperature decreases, the transition of SF → TQA → triplet-triplet annihilation (TTA) and TQA coexistence → TTA process occurs. Moreover, MEL responses of the TmPyPb-ETL device show a W-linear pattern owing to the combined effect of the hyperfine interaction (HFI) and Zeeman splitting at 145 K. Accordingly, we explored the electroluminescence (EL) performance of TmPyPB-ETL OLEDs and investigated the evolution of SF, TQA, and TTA processes using MEL. Our study revealed the effect of exciton recombination and annihilation in OLEDs with varying thicknesses of TmPyPb.

Microstructure Evolution and Deformation Behavior of Extruded Mg-5Al-0.6Sc Alloy during Room and Elevated Temperature Tension Revealed by Ex-Situ EBSD and VPSC.

In this study, the microstructure evolution and deformation behavior of the extruded Mg-5Al-0.6Sc (AS51) alloy during tensile testing at room temperature (RT) and 250 °C were investigated by electron backscattered diffraction (EBSD) characterization and Visco Plastic Self Consistent (VPSC) simulation. The results showed that a continuous hardening behavior of the alloy occurred during the deformation at RT, and a certain softening was caused by the occurrence of dynamic recovery (DRV) and dynamic recrystallization (DRX) in the late stage of deformation at 250 °C. The primary deformation mechanism at both RT and 250 °C was dislocation slip, with prismatic slip being the dominant deformation mode, and no significant changes in grain size or texture type occurred. By identifying the activated twin variants, the results indicated that the selection of twin variants was closely related to the local stress concentration. The relatively low activation frequency of extension twinning at 250 °C is partly attributed to the fact that the consumption of dislocations by DRV and DRX can effectively relax the local stress concentration. Meanwhile, the DRX mechanism during the deformation of the alloy at 250 °C was mainly discontinuous dynamic recrystallization (DDRX), with a low recrystallization fraction.

Synthesis of Aryl Amides from Acyl-Bunte Salts and Aryl Azides.

In this study, we developed an efficient method for the synthesis of aryl amides from sodium thiosulfate pentahydrate, organic anhydrides, and aryl azides. Sodium thiosulfate may be used as the sulfur source, which reacts with anhydrides to generate acyl-Bunte salt; this salt reacts with aryl azides via the in situ generation of thiocarboxylate. Using our method, we successfully synthesized a key bioactive compound. The advantages of one-pot two-step reactions include operational simplicity, structurally diverse products with favorable yields, use of less toxic odorless reagents, and easy applicability to large-scale operations.

Can Axillary Lymph Node Dissection be Omitted in Breast Cancer Patients with Metastatic Sentinel Lymph Nodes Undergoing Mastectomy? A Systematic Review and Meta-Analysis of Real-World Evidence.

BACKGROUND: The omission of axillary lymph node dissection (ALND) in patients with breast cancer who have metastatic sentinel lymph nodes (SLNs) undergoing mastectomy remains controversial. This meta-analysis explored the clinicopathological factors affecting the selection of ALND and the influences of ALND on survival outcomes in patients receiving mastectomy with positive SLNs. METHODS: Eligible studies published prior to 31 December 2022 were selected by searching the Embase, Web of Science and PubMed databases. Pooled analyses were performed using the number of events for clinicopathological parameters and HRs with 95% CIs for survival outcomes including disease-free survival (DFS), overall survival (OS), distant recurrence-free survival (DRFS) and locoregional recurrence-free survival (LRFS). RESULTS: A total of 10 retrospective studies enrolling only breast cancer patients with limited SLN metastases (no more than 3 positive SLNs or micrometastatic SLNs) undergoing mastectomy were included. Performing ALND in mastectomy patients who had limited SLN metastases was significantly correlated with invasive ductal carcinomas, larger tumors, lymphovascular invasion, higher tumor grade, macrometastatic SLNs, more positive SLNs, extranodal extension, positive surgical margins, negative ER, administration of adjuvant chemotherapy and nonwhite race (P < 0.05). However, performing ALND did not result in significantly longer OS, DFS, LRFS or DRFS (P > 0.05) in these patients. CONCLUSION: The present meta-analysis indicated that ALND may be safely avoided in patients with breast cancer who had limited SLN metastases undergoing mastectomy. Further well-designed randomized clinical trials are warranted to validate our results.

p53 deacetylation alleviates calcium oxalate deposition-induced renal fibrosis by inhibiting ferroptosis.

Calcium oxalate (CaOx) stones are among the most common types of kidney stones and are associated with renal tubular damage, interstitial fibrosis, and chronic kidney disease. The mechanism of CaOx crystal-induced renal fibrosis remains unknown. Ferroptosis, a type of regulated cell death, is characterised by iron-dependent lipid peroxidation, and the tumour suppressor p53 is a key regulator of ferroptosis. In the present study, our results demonstrated that ferroptosis was significantly activated in patients with nephrolithiasis and hyperoxaluric mice as well as verified the protective effects of ferroptosis inhibition on CaOx crystal-induced renal fibrosis. Moreover, the single-cell sequencing database, RNA-sequencing, and western blot analysis revealed that the expression of p53 was increased in patients with chronic kidney disease and the oxalate-stimulated human renal tubular epithelial cell line, HK-2. Additionally, the acetylation of p53 was enhanced by oxalate stimulation in HK-2 cells. Mechanistically, we found that the induction of p53 deacetylation, owing to either the SRT1720-induced activation of deacetylase sirtuin 1 or the triple mutation of p53, inhibited ferroptosis and alleviated renal fibrosis caused by CaOx crystals. We conclude that ferroptosis is one of the critical mechanisms contributing to CaOx crystal-induced renal fibrosis, and the pharmacological induction of ferroptosis via sirtuin 1-mediated p53 deacetylation may be a potential target for preventing renal fibrosis in patients with nephrolithiasis.

Structures, Sources, Identification/Quantification Methods, Health Benefits, Bioaccessibility, and Products of Isorhamnetin Glycosides as Phytonutrients.

In recent years, people have tended to consume phytonutrients and nutrients in their daily diets. Isorhamnetin glycosides (IGs) are an essential class of flavonoids derived from dietary and medicinal plants such as Opuntia ficus-indica, Hippophae rhamnoides, and Ginkgo biloba. This review summarizes the structures, sources, quantitative and qualitative analysis technologies, health benefits, bioaccessibility, and marketed products of IGs. Routine and innovative assay methods, such as IR, TLC, NMR, UV, MS, HPLC, UPLC, and HSCCC, have been widely used for the characterization and quantification of IGs. All of the therapeutic effects of IGs discovered to date are collected and discussed in this study, with an emphasis on the relevant mechanisms of their health-promoting effects. IGs exhibit diverse biological activities against cancer, diabetes, hepatic diseases, obesity, and thrombosis. They exert therapeutic effects through multiple networks of underlying molecular signaling pathways. Owing to these benefits, IGs could be utilized to make foods and functional foods. IGs exhibit higher bioaccessibility and plasma concentrations and longer average residence time in blood than aglycones. Overall, IGs as phytonutrients are very promising and have excellent application potential.

Discovery of N-sulfonylated aminosalicylic acids as dual MCL-1/BCL-xL inhibitors.

The anti-apoptotic protein MCL-1, which is overexpressed in multiple cancers, is presently a focus for the development of targeted drugs in oncology. We previously discovered inhibitors of MCL-1 based on 1-sulfonylated 1,2,3,4-tetrahydroquinoline-6-carboxylic acids ("1,6-THQs"). However, with the nitrogen atom constrained in the bicyclic ring, we were unable to modify the alkyl portion of the tertiary sulfonamide functionality. Moreover, the introduction of additional functional groups onto the benzene ring portion of the THQ bicycle would not be trivial. Therefore, we elected to deconstruct the piperidine-type ring of the 6-carboxy-THQ lead to create a new 4-aminobenzoic acid scaffold. Given its simplicity, this permitted us to introduce diversity at the sulfonamide nitrogen, as well as vary the positions and substituents of the benzene ring. One of our most potent MCL-1 inhibitors, 6e-OH, exhibited a K i of 0.778 µM. Heteronuclear single quantum coherence experiments suggested 6e-OH bound in the canonical BH3-binding groove, with significant perturbations of R263, which forms a salt bridge with MCL-1's pro-apoptotic binding partners, as well as residues in the p2 pocket. Selectivity studies indicated that our compounds are dual inhibitors of MCL-1 and BCL-xL, with 17cd the most potent dual inhibitor: K i = 0.629 µM (MCL-1), 1.67 µM (BCL-xL). Whilst selective inhibitors may be more desirable in certain instances, polypharmacological agents whose additional target(s) address other pathways associated with the disease state, or serve to counter resistance mechanisms to the primary target, may prove particularly effective therapeutics. Since selective MCL-1 inhibition may be thwarted by overexpression of sister anti-apoptotic proteins, including BCL-xL and BCL-2, we believe our work lays a solid foundation towards the development of multi-targeting anti-cancer drugs.