Self-reporting intracellular delivery agent for singlet oxygen.

1,4-Dimethylphenazine endoperoxide releases singlet oxygen with a half-life of 89 hours at 37 °C. The thermal cycloreversion reaction is accompanied by a strong increase in the emission intensity with a peak at 490 nm, due to the formation of the phenazine core. The endoperoxide is effective against cancer cells in culture medium and tumor spheroids, with singlet oxygen-mediated cytotoxicity.

N-Phenyl-2-Pyridone-Derived Endoperoxide Suppressing both Lung Cancer and Idiopathic Pulmonary Fibrosis Progression by Three-Pronged Action.

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone, thus targeting multiple mechanisms for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half-life of 8.3 hours without the generation of other by-products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of HIF-1α protein, but also inhibits the TGF-ß1 induced fibrosis in vitro. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3-methyl-N-phenyl-2-pyridone, and triplet oxygen could downregulate HIF-1α and relieve tumor hypoxia which is a critical issue in conventional PDT. Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases.

USP36 inhibits apoptosis by deubiquitinating cIAP1 and survivin in colorectal cancer cells.

Chemotherapeutic agents for treating colorectal cancer (CRC) primarily induce apoptosis in tumor cells. The ubiquitin-proteasome system is critical for apoptosis regulation. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrates to reverse ubiquitination. Although over 100 DUB members have been discovered, the biological functions of only a small proportion of DUBs have been characterized. Here, we aimed to systematically identify the DUBs that contribute to the development of CRC. Among the DUBs, ubiquitin-specific protease 36 (USP36) is upregulated in CRC. We showed that the knockdown of USP36 induces intrinsic and extrinsic apoptosis. Through gene silencing and coimmunoprecipitation techniques, we identified survivin and cIAP1 as USP36 targets. Mechanistically, USP36 binds and removes lysine-11-linked ubiquitin chains from cIAP1 and lysine-48-linked ubiquitin chains from survivin to abolish protein degradation. Overexpression of USP36 disrupts the formation of the XIAP-second mitochondria-derived activator of caspase complex and promotes receptor-interacting protein kinase 1 ubiquitination, validating USP36 as an inhibitor to intrinsic and extrinsic apoptosis through deubiquitinating survivin and cIAP1. Therefore, our results suggest that USP36 is involved in CRC progression and is a potential therapeutic target.

Herb pair of Huangqi-Danggui exerts anti-tumor immunity to breast cancer by upregulating PIK3R1.

BACKGROUND: According to traditional Chinese medicine (TCM), drugs supplementing the vital energy, Qi, can eliminate tumors by restoring host immunity. The objective of this study is to investigate the underlying immune mechanisms of anti-tumor activity associated with Qi-supplementing herbs, specifically the paired use of Huangqi and Danggui. METHODS: Analysis of compatibility regularity was conducted to screen the combination of Qi-supplementing TCMs. Using the MTT assay and a transplanted tumor mice model, the anti-tumor effects of combination TCMs were investigated in vitro and in vivo. High content analysis and flow cytometry were then used to evaluate cellular immunity, followed by network pharmacology and molecular docking to dissect the significant active compounds and potential mechanisms. Finally, the anti-tumor activity and the mechanism of the active ingredients were verified by molecular experiments. RESULTS: There is an optimal combination of Huangqi and Danggui that, administered as an aqueous extract, can activate immunity to suppress tumor and is more effective than each drug on its own in vitro and in vivo. Based on network pharmacology analysis, PIK3R1 is the core target for the anti-tumor immunity activity of combined Huangqi and Danggui. Molecular docking analysis shows 6 components of the combined Danggui and Huangqi extract (quercetin, jaranol, isorhamnetin, kaempferol, calycosin, and suchilactone) that bind to PIK3R1. Jaranol is the most important component against breast cancer. The suchilactone/jaranol combination and, especially, the suchilactone/kaempferol combination are key for immunity enhancement and the anti-tumor effects of the extract. CONCLUSIONS: The combination of Huangqi and Danggui can activate immunity to suppress breast cancer and is more effective than the individual drugs alone.

Intestinal NSD2 Aggravates Nonalcoholic Steatohepatitis Through Histone Modifications.

Mounting clinical evidence suggests that a comprised intestinal barrier contributes to the progression of nonalcoholic steatohepatitis (NASH); nevertheless, the precise mechanism remains elusive. This study unveils a significant upregulation of nuclear receptor-binding SET domain protein 2 (NSD2) in the intestines of obese humans and mice subjected to a high-fat cholesterol diet (HFCD). Intestine-specific NSD2 knockout attenuated the progression of intestinal barrier impairment and NASH, whereas NSD2 overexpression exacerbated this progression. Mechanistically, NSD2 directly regulates the transcriptional activation of Ern1 by demethylating histone H3 at lysine 36 (H3K36me2), thus activating the ERN1-JNK axis to intensify intestinal barrier impairment and subsequently foster NASH progression. These findings elucidate the crucial role of NSD2-mediated H3K36me2 in intestinal barrier impairment, suggesting that targeting intestinal NSD2 can represent a novel therapeutic approach for NASH.

Association between household size and risk of incident dementia in the UK Biobank study.

Currently, the relationship between household size and incident dementia, along with the underlying neurobiological mechanisms, remains unclear. This prospective cohort study was based on UK Biobank participants aged ≥ 50 years without a history of dementia. The linear and non-linear longitudinal association was assessed using Cox proportional hazards regression and restricted cubic spline models. Additionally, the potential mechanisms driven by brain structures were investigated by linear regression models. We included 275,629 participants (mean age at baseline 60.45 years [SD 5.39]). Over a mean follow-up of 9.5 years, 6031 individuals developed all-cause dementia. Multivariable analyses revealed that smaller household size was associated with an increased risk of all-cause dementia (HR, 1.06; 95% CI 1.02-1.09), vascular dementia (HR, 1.08; 95% CI 1.01-1.15), and non-Alzheimer's disease non-vascular dementia (HR, 1.09; 95% CI 1.03-1.14). No significant association was observed for Alzheimer's disease. Restricted cubic splines demonstrated a reversed J-shaped relationship between household size and all-cause and cause-specific dementia. Additionally, substantial associations existed between household size and brain structures. Our findings suggest that small household size is a risk factor for dementia. Additionally, brain structural differences related to household size support these associations. Household size may thus be a potential modifiable risk factor for dementia.

Structurally diverse isoquinoline alkaloids from the barks of Alangium salviifolium (L. f.) Wangerin and their cytotoxicity.

Eleven undescribed isoquinoline alkaloids (1-8, 14, 15, and 24), along with 19 analogues (9-13, 16-23, and 25-30) were isolated from the barks of Alangium salviifolium. The structures of the undescribed compounds were elucidated through the analysis of their HR-ESI-MS, 1D and 2D NMR, IR, UV, and X-ray diffraction. The absolute configuration of 8 was established via the ECD calculation. Notably, compounds 1/2 and 3/4 were two pairs of C-14 epimers. The isolated alkaloids were evaluated for their cytotoxicity against various cancer cell lines, including SGC-7901, HeLa, K562, A549, BEL-7402, HepG2, and B16, ß-carboline-benzoquinolizidine (14-22) and cepheline-type (24-28) alkaloids exhibited remarkable cytotoxicity, with IC50 values ranging from 0.01 to 48.12 µM. Remarkably, compounds 17 and 21 demonstrated greater cytotoxicity than the positive control doxorubicin hydrochloride. Furthermore, a significant proportion of these bioactive alkaloids possess a C-1' epimer configuration. The exploration of their structure-activity relationship holds promise for directing future investigations into alkaloids derived from Alangium, potentially leading to novel insights and therapeutic advancements.

Correction: A closer look at ligand specificity for cellular activation of NOD2 with synthetic muramyl dipeptide analogues.

Correction for 'A closer look at ligand specificity for cellular activation of NOD2 with synthetic muramyl dipeptide analogues' by Christopher Adamson et al., Chem. Commun., 2024, 60, 2212-2215, https://doi.org/10.1039/D3CC05807G.

GlcNAc-1,6-anhydro-MurNAc Moiety Affords Unusual Glycosyl Acceptor that Terminates Peptidoglycan Elongation.

Peptidoglycan (PG), an essential exoskeletal polymer in bacteria, is a well-known antibiotic target. PG polymerization requires the action of bacterial transglycosylases (TGases), which couple the incoming glycosyl acceptor to the donor. Interfering with the TGase activity can interrupt the PG assembly. Existing TGase inhibitors like moenomycin and Lipid II analogues always occupy the TGase active sites; other strategies to interfere with proper PG elongation have not been widely exploited. Inspired by the natural 1,6-anhydro-MurNAc termini that mark the ends of PG strands in bacteria, we hypothesized that the incorporation of an anhydromuramyl-containing glycosyl acceptor by TGase into the growing PG may effectively inhibit PG elongation. To explore this possibility, we synthesized 4-O-(N-acetyl-ß-d-glucosaminyl)-1,6-anhydro-N-acetyl-ß-d-muramyl-l-Ala-γ-d-Glu-l-Lys-d-Ala-d-Ala, 1, within 15 steps, and demonstrated that this anhydromuropeptide and its analogue lacking the peptide, 1-deAA, were both utilized by bacterial TGase as noncanonical anhydro glycosyl acceptors in vitro. The incorporation of an anhydromuramyl moiety into PG strands by TGases afforded efficient termination of glycan chain extension. Moreover, the preliminary in vitro studies of 1-deAA against Staphylococcus aureus showed that 1-deAA served as a reasonable antimicrobial adjunct of vancomycin. These insights imply the potential application of such anhydromuropeptides as novel classes of PG-terminating inhibitors, pointing toward novel strategies in antibacterial agent development.

Extranodal Extension at Pretreatment MRI and the Prognostic Value for Patients with Rectal Cancer.

Background Detection of extranodal extension (ENE) at pathology is a poor prognostic indicator for rectal cancer, but whether ENE can be identified at pretreatment MRI is, to the knowledge of the authors, unknown. Purpose To evaluate the performance of pretreatment MRI in detecting ENE using a matched pathologic reference standard and to assess its prognostic value in patients with rectal cancer. Materials and Methods This single-center study included a prospective development data set consisting of participants with rectal adenocarcinoma who underwent pretreatment MRI and radical surgery (December 2021 to January 2023). MRI characteristics were identified by their association with ENE-positive nodes (χ2 test and multivariable logistic regression) and the performance of these MRI features was assessed (area under the receiver operating characteristic curve [AUC]). Interobserver agreement was assessed by Cohen κ coefficient. The prognostic value of ENE detected with MRI for predicting 3-year disease-free survival was assessed by Cox regression analysis in a retrospective independent validation cohort of patients with locally advanced rectal cancer (December 2019 to July 2020). Results The development data set included 147 participants (mean age, 62 years ± 11 [SD]; 87 male participants). The retrospective cohort included 110 patients (mean age, 60 years ± 9; 79 male participants). Presence of vessel interruption and fusion (both P < .001), heterogeneous internal structure, and the broken-ring and tail signs (odds ratio range, 4.10-23.20; P value range, <.001 to .002) were predictors of ENE at MRI, and together achieved an AUC of 0.91 (95% CI: 0.88, 0.93) in detecting ENE. Interobserver agreement was moderate for the presence of vessel interruption and fusion (κ = 0.46 for both) and substantial for others (κ = 0.61-0.67). The presence of ENE at pretreatment MRI was independently associated with worse 3-year disease-free survival (hazard ratio, 3.00; P = .02). Conclusion ENE can be detected at pretreatment MRI, and its presence was associated with worse prognosis for patients with rectal cancer. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Eberhardt in this issue.

Predictive value of coagulation function, alpha-fetoprotein and placental growth factor in patients with perilous placenta previa.

OBJECTIVE: To analyze the predictive value of coagulation function, alpha-fetoprotein (AFP) and placental growth factor (PIGF) for postpartum hemorrhage in patients with perilous placenta previa (PPP). METHODS: The clinical data of 104 PPP patients were retrospectively analyzed. The patients were divided into a hemorrhage group (n=68) and a non-hemorrhage group (n=36). A total of 55 healthy pregnant women were recruited as controls. The coagulation function, AFP and PIGF were compared between the three groups. Multivariate logistic regression was performed to determine independent risk factors for hemorrhage. RESULTS: PT, TT, APTT, FIB and AFP were significantly higher while PIGF was lower in the PPP group than the control group (all P<0.05). Placental adhesion (OR 3.924, 95% CI 1.389-11.083, P=0.01), anterior placenta (OR 4.583, 95% CI 1.589-13.22, P=0.005), AFP (OR 0.208, 95% CI 0.068-0.635, P=0.006) and PIGF (OR 3.963, 95% CI 1.385-11.34, P=0.01) were independent risk factors for hemorrhage. CONCLUSION: Coagulation function, AFP and PIGF could predict postpartum hemorrhage in PPP patients.

Joint Exposure to Ambient Air Pollutants, Genetic Risk, and Ischemic Stroke: A Prospective Analysis in UK Biobank.

BACKGROUND: Our primary objective was to assess the association between joint exposure to various air pollutants and the risk of ischemic stroke (IS) and the modification of the genetic susceptibility. METHODS: This observational cohort study included 307 304 British participants from the United Kingdom Biobank, who were stroke-free and possessed comprehensive baseline data on genetics, air pollutant exposure, alcohol consumption, and dietary habits. All participants were initially enrolled between 2006 and 2010 and were followed up until 2022. An air pollution score was calculated to assess joint exposure to 5 ambient air pollutants, namely particulate matter with diameters equal to or <2.5 µm, ranging from 2.5 to 10 µm, equal to or <10 µm, as well as nitrogen oxide and nitrogen dioxide. To evaluate individual genetic risk, a polygenic risk score for IS was calculated for each participant. We adjusted for demographic, social, economic, and health covariates. Cox regression models were utilized to estimate the associations between air pollution exposure, polygenic risk score, and the incidence of IS. RESULTS: Over a median follow-up duration of 13.67 years, a total of 2476 initial IS events were detected. The hazard ratios (95% CI) of IS for per 10 µg/m3 increase in particulate matter with diameters equal to or <2.5 µm, ranging from 2.5 to 10 µm, equal to or <10 µm, nitrogen dioxide, and nitrogen oxide were 1.73 (1.33-2.14), 1.24 (0.88-1.70), 1.13 (0.89-1.33), 1.03 (0.98-1.08), and 1.04 (1.02-1.07), respectively. Furthermore, individuals in the highest quintile of the air pollution score exhibited a 29% to 66% higher risk of IS compared with those in the lowest quintile. Notably, participants with both high polygenic risk score and air pollution score had a 131% (95% CI, 85%-189%) greater risk of IS than participants with low polygenic risk score and air pollution score. CONCLUSIONS: Our findings suggested that prolonged joint exposure to air pollutants may contribute to an increased risk of IS, particularly among individuals with elevated genetic susceptibility to IS.

In silico MS/MS prediction for peptidoglycan profiling uncovers novel anti-inflammatory peptidoglycan fragments of the gut microbiota.

Peptidoglycan is an essential exoskeletal polymer across all bacteria. Gut microbiota-derived peptidoglycan fragments (PGNs) are increasingly recognized as key effector molecules that impact host biology. However, the current peptidoglycan analysis workflow relies on laborious manual identification from tandem mass spectrometry (MS/MS) data, impeding the discovery of novel bioactive PGNs in the gut microbiota. In this work, we built a computational tool PGN_MS2 that reliably simulates MS/MS spectra of PGNs and integrated it into the user-defined MS library of in silico PGN search space, facilitating automated PGN identification. Empowered by PGN_MS2, we comprehensively profiled gut bacterial peptidoglycan composition. Strikingly, the probiotic Bifidobacterium spp. manifests an abundant amount of the 1,6-anhydro-MurNAc moiety that is distinct from Gram-positive bacteria. In addition to biochemical characterization of three putative lytic transglycosylases (LTs) that are responsible for anhydro-PGN production in Bifidobacterium, we established that these 1,6-anhydro-PGNs exhibit potent anti-inflammatory activity in vitro, offering novel insights into Bifidobacterium-derived PGNs as molecular signals in gut microbiota-host crosstalk.

A closer look at ligand specificity for cellular activation of NOD2 with synthetic muramyl dipeptide analogues.

To further understand the specificity of muramyl dipeptide (MDP) sensing by NOD2, we evaluated the compatibility of synthetic MDP analogues for cellular uptake and NAGK phosphorylation, the pre-requisite steps of intracellular NOD2 activation. Our results revealed that these two prior steps do not confer ligand stereoselectivity; yet NAGK strictly discriminates against the disaccharide NOD2 agonists for phosphorylation in vitro, despite it being indispensable for the cellular NOD2-stimulating effects of these analogues, implying potential glycosidase cleavage as a novel intermediate step for cellular activation of NOD2.

Type 1 and type 2 diabetes mortality burden: Predictions for 2030 based on Bayesian age-period-cohort analysis of China and global mortality burden from 1990 to 2019.

AIMS: This study assessed diabetes (type 1 and type 2) mortality in China and globally from 1990 to 2019, predicting the next decade's trends. MATERIALS AND METHODS: Data came from the Global Burden of Disease (GBD) database. The annual percentage change (AAPC) in age-standardized mortality rates (ASMR) for diabetes (type 1 and type 2) during 1990-2019 was calculated. A Bayesian age-period-cohort (BAPC) model predicted diabetes (type 1 and type 2) mortality from 2020 to 2030. RESULTS: In China, type 1 diabetes deaths declined from 6,005 to 4,504 cases (AAPC -2.827), while type 2 diabetes deaths rose from 64,084 to 168,388 cases (AAPC -0.763) from 1990 to 2019. Globally, type 1 diabetes deaths increased from 55,417 to 78,236 cases (AAPC 0.223), and type 2 diabetes deaths increased from 606,407 to 1,472,934 cases (AAPC 0.365). Both China and global trends showed declining type 1 diabetes ASMR. However, female type 2 diabetes ASMR in China initially increased and then decreased, while males had a rebound trend. Peak type 1 diabetes deaths were in the 40-44 age group, and type 2 diabetes peaked in those over 70. BAPC predicted declining diabetes (type 1 and type 2) mortality burden in China and globally over the next 10 years. CONCLUSIONS: Type 2 diabetes mortality remained high in China and globally despite decreasing type 1 diabetes mortality over 30 years. Predictions suggest a gradual decrease in diabetes mortality over the next decade, highlighting the need for continued focus on type 2 diabetes prevention and treatment.

Methionine redox regulation of actin-interacting proteins primarily governs antioxidative signaling and response to the salvianolic acid B treatment in EA.hy926 cells.

Actin-interacting proteins are important molecules for filament assembly and cytoskeletal signaling within vascular endothelium. Disruption in their interactions causes endothelial pathogenesis through redox imbalance. Actin filament redox regulation remains largely unexplored, in the context of pharmacological treatment. This work focused on the peptidyl methionine (M) redox regulation of actin-interacting proteins, aiming at elucidating its role on governing antioxidative signaling and response. Endothelial EA.hy926 cells were subjected to treatment with salvianolic acid B (Sal B) and tert-butyl-hydroperoxide (tBHP) stimulation. Mass spectrometry was employed to characterize redox status of proteins, including actin, myosin-9, kelch-like erythroid-derived cap-n-collar homology-associated protein 1 (Keap1), plastin-3, prelamin-A/C and vimentin. The protein redox landscape revealed distinct stoichiometric ratios or reaction site transitions mediated by M sulfoxide reductase and reactive oxygen species. In comparison with effects of tBHP stimulation, Sal B treatment prevented oxidation at actin M325, myosin-9 M1489/1565, Keap1 M120, plastin-3 M592, prelamin-A/C M187/371/540 and vimentin M344. For Keap1, reaction site was transitioned within its scaffolding region to the actin ring. These protein M oxidation regulations contributed to the Sal B cytoprotective effects on actin filament. Additionally, regarding the Keap1 homo-dimerization region, Sal B preventive roles against M120 oxidation acted as a primary signal driver to activate nuclear factor erythroid 2-related factor 2 (Nrf2). Transcriptional splicing of non-POU domain-containing octamer-binding protein was validated during the Sal B-mediated overexpression of NAD(P)H dehydrogenase [quinone] 1. This molecular redox regulation of actin-interacting proteins provided valuable insights into the phenolic structures of Sal B analogs, showing potential antioxidative effects on vascular endothelium.

A model to predict delivery time following induction of labor at term with a dinoprostone vaginal insert: a retrospective study.

BACKGROUND: Dinoprostone vaginal insert is the most common pharmacological method for induction of labor (IOL); however, studies on assessing the time to vaginal delivery (DT) following dinoprostone administration are limited. AIMS: We sought to identify the primary factors influencing DT in women from central China, at or beyond term, who underwent IOL with dinoprostone vaginal inserts. METHODS: In this retrospective observational study, we analyzed the data of 1562 women at 37 weeks 0 days to 41 weeks 6 days of gestation who underwent dinoprostone-induced labor between January 1st, 2019, and December 31st, 2021. The outcomes of interest were vaginal or cesarean delivery and factors influencing DT, including maternal complications and neonatal characteristics. RESULTS: Among the enrolled women, 71% (1109/1562) delivered vaginally, with median DT of 740.50 min (interquartile range 443.25 to 1264.50 min). Of the remaining 29% (453/1562), who delivered by cesarean section, 11.9% (54/453) were multiparous. Multiple linear regression analysis showed that multiparity, advanced maternal age, fetal macrosomia, premature rupture of membranes (PROM), and daytime insertion of dinoprostone were the factors that significantly influenced DT. Time to vaginal delivery increased with advanced maternal age and fetal macrosomia and decreased with multiparity, PROM, and daytime insertion of dinoprostone. A mathematical model was developed to integrate these factors for predicting DT: Y = 804.478 - 125.284 × multiparity + 765.637 × advanced maternal age + 411.511 × fetal macrosomia-593.358 × daytime insertion of dinoprostone - 125.284 × PROM. CONCLUSIONS: Our findings may help obstetricians estimate the DT before placing a dinoprostone insert, which may improve patient management in busy maternity wards and minimize potential risks.

A novel SLC25A1 inhibitor, parthenolide, suppresses the growth and stemness of liver cancer stem cells with metabolic vulnerability.

Liver cancer stem cells (LCSCs) are recognized as key contributors to hepatocarcinogenesis, progression, and recurrence. Consequently, eradicating LCSCs has a great chance of increasing long-term survival in patients with liver cancer. Parthenolide (PTL), a natural sesquiterpene lactone product, possesses robust antitumor activity. However, the effects of PTL on LCSCs and underlying mechanisms remain unknown. Here we show that administration of PTL stimulated cell cycle arrest at the G1 phase, induced apoptosis, and decreased the stemness of LCSCs. Further research indicates that PTL caused the production of ROS and the reduction of oxidative phosphorylation (OXPHOS) and mitochondrial membrane potential (MMP) levels of LCSCs. RNA sequencing (RNA-Seq) further shows that PTL decreased SLC25A1 expression at the mRNA level and that inhibition of SLC25A1 synergistically decreased the expression of IDH2 and several pivotal genes involved in mitochondrial respiratory chain complex, resulting in the production of ROS and mitochondrial dysfunction. In addition, the inhibitory effect of PTL on mitochondrial function and self-renewal capacity of LCSCs was abolished by the knockdown of SLC25A1 or treatment with SLC25A1 inhibitor CTPI-2. Importantly, PTL prevented liver cancer growth in vivo without clearly causing toxicity. Our research shows that PTL inhibits the growth and stemness of LCSCs through SLC25A1-mediated mitochondrial function. PTL may be a potential candidate natural agent for liver cancer treatment.

Oxidative stress and inflammation in diabetic nephropathy: role of polyphenols.

Diabetic nephropathy (DN) often leads to end-stage renal disease. Oxidative stress demonstrates a crucial act in the onset and progression of DN, which triggers various pathological processes while promoting the activation of inflammation and forming a vicious oxidative stress-inflammation cycle that induces podocyte injury, extracellular matrix accumulation, glomerulosclerosis, epithelial-mesenchymal transition, renal tubular atrophy, and proteinuria. Conventional treatments for DN have limited efficacy. Polyphenols, as antioxidants, are widely used in DN with multiple targets and fewer adverse effects. This review reveals the oxidative stress and oxidative stress-associated inflammation in DN that led to pathological damage to renal cells, including podocytes, endothelial cells, mesangial cells, and renal tubular epithelial cells. It demonstrates the potent antioxidant and anti-inflammatory properties by targeting Nrf2, SIRT1, HMGB1, NF-κB, and NLRP3 of polyphenols, including quercetin, resveratrol, curcumin, and phenolic acid. However, there remains a long way to a comprehensive understanding of molecular mechanisms and applications for the clinical therapy of polyphenols.

Association between hypoproteinaemia with massive proteinuria and small for gestational age in pre-eclampsia: a single-centre, retrospective cohort study using propensity score matching.

OBJECTIVE: To investigate the association between hypoproteinaemia with massive proteinuria and the incidence of small for gestational age in pre-eclampsia. DESIGN: Retrospective cohort study using propensity score matching. SETTING: Northwest Women's and Children's Hospital in Shaanxi Province, China, using data from January 2016 to December 2021. PARTICIPANTS: Patients diagnosed with pre-eclampsia were grouped into the massive proteinuria group if the maximum proteinuria was >3.5 g/day and the minimum serum albumin was <30 g/L; otherwise, they were placed in the control group. OUTCOME MEASURES: The primary outcome was the incidence of small for gestational age infants. Secondary outcomes included fetal death, admission to the neonatal intensive care unit, a 5 min APGAR score <7, severe small for gestational age, fetal growth restriction, birth weight, premature birth, and maternal outcomes such as eclampsia, encephalopathy, placental abruption, haemolysis, elevated liver enzymes and low platelet syndrome, heart failure and retinal detachment. RESULTS: In total, 468 patients (234 from each group) were included, and the groups were well matched. The incidences of small for gestational age (33.76% vs 20.51%, OR 1.646, 95% CI 1.208 to 2.243, p=0.001), severe small for gestational age (14.70% vs 7.69%, OR 1.833, 95% CI 1.063 to 3.162, p=0.026), fetal growth restriction (23.93% vs 16.24%, OR 1.474, 95% CI 1.018 to 2.133, p=0.038), and the numbers of infants admitted to the neonatal intensive care unit (67.52% vs 58.55%, OR 1.153, 95% CI 1.003 to 1.326, p=0.044) were significantly higher in patients with hypoproteinaemia and massive proteinuria than in the control group. In addition, the median birth weight was significantly lower in the massive proteinuria group. There were no significant differences in maternal outcomes except for renal parameters, which were worse in the massive proteinuria group. CONCLUSION: Hypoproteinaemia with massive proteinuria was associated with fetal growth and a higher incidence of small for gestational age infants in pre-eclampsia.