Joint effects of air pollution and genetic susceptibility on incident primary open-angle glaucoma.

BACKGROUND: Air pollutants are important exogenous stimulants to eye diseases, but knowledge of associations between long-term exposure to air pollutants and the risk of primary open-angle glaucoma (POAG) is limited. This study aimed to determine whether long-term exposure to air pollutants, genetic susceptibility, and their joint effects lead to an elevated risk of incident POAG. METHODS: This is a population-based prospective cohort study from UK Biobank participants with complete measures of air pollution exposure and polygenetic risk scores. Cox proportional hazard models were fitted to assess the individual and joint effects of long-term exposure to air pollutants and genetics on the risk of POAG. In addition, the effect modification of genetic susceptibility was examined on an additive or multiplicative scale. RESULTS: Among 434,290 participants with a mean (SD) age of 56.5 (8.1) years, 6651 (1.53 %) were diagnosed with POAG during a median follow-up of 13.7 years. Long-term exposure to air pollutants was associated with an increased risk of POAG. The hazard ratios associated with per interquartile range increase in PM2.5, PM2.5 absorbance, PM10, NO2, and NOX individually ranged from 1.027 (95 % CI: 1.001-1.054) to 1.067 (95 % CI: 1.035-1.099). Compared with individuals residing in low-pollution areas and having low polygenic risk scores, the risk of incident POAG increased by 105.5 % (95 % CI: 78.3 %-136.9 %), 79.7 % (95 % CI: 56.5 %-106.5 %), 103.2 % (95 % CI: 76.9 %-133.4 %), 89.4 % (95 % CI: 63.9 %-118.9 %), and 90.2 % (95 % CI: 64.8 %-119.5 %) among those simultaneously exposed to high air pollutants levels and high genetic risk, respectively. Genetic susceptibility interacted with PM2.5 absorbance and NO2 in an additive manner, while no evidence of multiplicative interaction was found in this study. Stratification analyses revealed stronger effects in Black people and the elderly. CONCLUSION: Long-term air pollutant exposure was associated with an increased risk of POAG incidence, particularly in the population with high genetic predisposition.

Novel Hsp90-Targeting PROTACs: Enhanced synergy with cisplatin in combination therapy of cervical cancer.

The development of effective drugs for cervical cancer is urgently required because of its high mortality rate and the limited treatment options. Herein, we report the design, synthesis, and evaluation of a series of novel and effective Hsp90-targeting PROTACs. These compounds exhibited potent anti-proliferative activity against cervical cancer cells with low IC50 values. Compound lw13 effectively degraded Hsp90 at a concentration of only 0.05 µM. In addition, it can inhibit the metastasis of cancer cells and induce significant cell cycle arrest and apoptosis. Furthermore, lw13 demonstrated remarkable antitumor activity both in vitro and in vivo, and has a synergistic effect in combination with cisplatin. Moreover, lw13 can prevent the activation of the HER2/AKT/mTOR signaling pathway by indirectly reducing the levels of HER2 and AKT. This study paves the way for cancer treatment and provides valuable insights into the combination therapy of cervical cancer.

[Effects of food waste biogas residue composting on soil aggregates and its organic matter content in relocation site]. / åŽ¨ä½™åžƒåœ¾æ²¼æ¸£å †è‚¥å¯¹æ¬è¿åœ°åœŸå£¤å›¢èšä½“åŠå ¶æœ‰æœºè´¨å«é‡çš„å½±å“.

Understanding the effects of food waste biogas residue composting and chemical amendments on soil aggregates composition of different particle sizes, stability, and organic matter distribution in relocation sites could provide primary data for improving soil quality and land utilization of food waste biogas residue composting. We analyzed the characteristics of soil aggregates distribution, stability of aggregates, and organic matter content in different particle sizes under treatments with different application amounts of food waste biogas residue composting, chemical amendments (ß-cyclodextrin, calcium sulfate and ferric oxide were mixed at a mass ratio of 1:1:1), and control (100% soil). The results showed that 20% (soil: biogas residue composting=8:2) and 30% (soil: biogas residue composting =7:3) biogas residue composting significantly decreased the micro-aggregates content with the particle size of <0.106 mm and increased the large aggregates content with the particle size of 0.5-1.0 mm. All treatments significantly increased large aggregates content with the particle size of ≥2.0 mm, soil aggregate structure content, and mean weight diameter, but reduced the percentage of aggregate destruction. Among all the treatments, the effect of mixes application of 20% biogas residue composting and chemical amendments was the best. Biogas residue composting treatments significantly affected the distribution of organic matter in soil aggregates, with the strongest effect under 30% biogas residue composting treatment. Biogas residue composting treatments significantly increased soil organic matter content in all aggregates, with the maximal increase of organic matter content in soil micro-aggregates with the particle size of 0.106-0.25 mm. In conclusion, biogas residue composting could increase organic matter content of soil aggregates in different particle sizes, promote the formation of large soil aggregates, and improve the stability of aggregation. Specifically, the mixed application of biogas residue composting and chemical amendments performed better on soil improvement in relocation site.

Novel Acyl Thiourea-Based Hydrophobic Tagging Degraders Exert Potent Anti-Influenza Activity through Two Distinct Endonuclease Polymerase Acidic-Targeted Degradation Pathways.

The spread of the influenza virus has caused devastating pandemics and huge economic losses worldwide. Antiviral drugs with diverse action modes are urgently required to overcome the challenges of viral mutation and drug resistance, and targeted protein degradation strategies constitute excellent candidates for this purpose. Herein, the first degradation of the influenza virus polymerase acidic (PA) protein using small-molecule degraders developed by hydrophobic tagging (HyT) technology to effectively combat the influenza virus was reported. The SAR results revealed that compound 19b with Boc2-(L)-Lys demonstrated excellent inhibitory activity against A/WSN/33/H1N1 (EC50 = 0.015 µM) and amantadine-resistant strain (A/PR/8/H1N1), low cytotoxicity, high selectivity, substantial degradation ability, and good drug-like properties. Mechanistic studies demonstrated that the proteasome system and autophagic lysosome pathway were the potential drivers of these HyT degraders. Thus, this study provides a powerful tool for investigating the targeted degradation of influenza virus proteins and for antiviral drug development.

Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer.

Estrogen receptor α (ERα) plays a pivotal role in the proliferation, differentiation, and migration of breast cancer (BC) cells, and aromatase (ARO) is a crucial enzyme in estrogen synthesis. Hence, it is necessary to inhibit estrogen production or the activity of ERα for the treatment of estrogen receptor-positive (ER+) BC. Herein, we present a new category of dual-targeting PROTAC degraders designed to specifically target ERα and ARO. Among them, compound 18c bifunctionally degrades and inhibits ERα/ARO, thus effectively suppressing the proliferation of MCF-7 cells while showing negligible cytotoxicity to normal cells. In vivo, 18c promotes the degradation of ERα and ARO and inhibits the growth of MCF-7 xenograft tumors. Finally, compound 18c demonstrates promising antiproliferative and ERα degradation activity against the ERαMUT cells. These findings suggest that 18c, being the inaugural dual-targeting degrader for ERα and ARO, warrants further advancement for the management of BC and the surmounting of endocrine resistance.

Picrachinentins A-F, 14-Membered Cyclopeptide Alkaloid-Type Burpitides with Uncommon N-Terminal Modifications from Picrasma chinensis and Their Neuroprotective Activity.

Picrachinentins A-F (1-6, respectively), six novel cyclopeptide alkaloid-type burpitides (CPABs), were isolated and fully elucidated from the EtOH extract of the stems and leaves of Picrasma chinensis. Structurally, compounds 1-6 have a 14-membered paracyclophane ring system that was closed through an ether bond between the ß-hydroxy amino acid and tyrosine and modified with a 4,5-methylenedioxybenzoyloxy (MDBz, 3 and 5) or hexanoyl (Hexa, 1, 2, 4, and 6) group at the N-terminus. Interestingly, this is the first report on the isolation and characterization of CPABs from plants of the Simaroubaceae family. In addition, all compounds showed a neuroprotective effect against H2O2-damaged SH-SY5Y cells. Compound 1 was further investigated for its neuroprotective activities using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease animal model, and it dramatically improved MPTP-impaired motor behavioral performance. Biochemical analysis revealed compound 1 restored the tyrosine hydroxylase expression in the striatum of the MPTP-damaged mouse brain, which demonstrates its protective effect on dopaminergic neurons.

[Comparative study of minimally invasive titanium elastic nail and steel plate on the treatment of fracture of tibiofibular fracture in adults].

OBJECTIVE: To compare the clinical outcomes of using elastic intramedullary nail and plate to fix fibular fracture. METHODS: The 60 patients with tibiofibular fractures admitted from January 2015 to December 2022 were divided into two groups:intramedullary nail group and plate group, 30 cases each, intramedullary nail group was treated with elastic intramedullary nail fixation group, plate group was treated with steel plate and screw fixation group. Intramedullary nail group, there were 18 males and 12 females, aged from 22 to 75 years old with an average of (39.4±9.8) years old, including 24 cases of traffic accidents injury, 6 cases of falling injury, 23 cases of closed fractures, 7 cases of open fractures. Steel plate group, there were 15 males and 15 females, aged from 24 to 78 years old with an average of (38.6±10.2) years old. The 22 cases were injured by traffic accident, 8 cases were injured by falling. The 24 cases were closed fractures and 6 cases were open fractures. The operation time, intraoperative bleeding, American Orthopedic Foot and Ankle Society (AOFAS) ankle and hind foot scores, clinical healing time of fibula and the incidence of wound complications were compared between the two groups. RESULTS: The patients in both groups were followed up for 6 to 21 months, with an average of (14.0±2.8) months. Compared with plate group, intramedullary nail group had shorter operative time, less bleeding, shorter clinical healing time of fibula, and lower infection rate of incision, and the difference was statistically significant (P<0.05). There were 2 cases of delayed healing in intramedullary nail group, 1 case of nonunion in plate group, and 2 cases of delayed healing in plate group, and there was no statistically significant difference between the two groups (P>0.05). In the last follow-up, according to the AOFAS scoring standard, the ankle function in intramedullary nail group was excellent in 17 cases, good in 12 cases, fair in 1 case, with an average of (88.33±4.57) points, while in plate group, excellent in 16 cases, good in 10 cases, fair in 4 cases, with an average of (87.00±4.14) points;There was no statistical difference between the two groups (P>0.05). CONCLUSION: Elastic intramedullary nail has the advantages of short operation time, less intraoperative bleeding, short fracture healing time and less incision complications in the treatment of fibular fracture, which is worthy of clinical application.

Change pattern and stability of oasisization land in Mu Us Sandy Land.

Understanding land structure change and stability in the process of oasisization is particularly important for the desertification control in sandy land. Based on land use data of eight periods from 1980 to 2020, we extracted the spatial distribution information of oasis land in Mu Us Sandy Land, and analyzed the spatio-temporal variations of land transformation patterns and stability of oasis land with overlay analysis and grid analysis. The results showed that desertification in the Mu Us Sandy Land had reversed, with a significant process of oasis. The area of forest and grassland increased from 10.2% in 1980 to 73.7% in 2020, while the area of oasisization land increased from 32500 km2 in 1980 to 33900 km2 in 2020. The area of extremely severe, severe, and moderate desertification significantly decreased, while the area of non-desertification and mild desertification obviously increased. The four patterns of oasisization land transformation, including stability, fluctuation, expansion, and retreat, which accounted for 78.7%, 12.2%, 6.2%, and 2.9% of the oasisization land area in 2020, respectively. The oasisization land with low change intensity (the cumulative change intensity less than 0.12) in the Mu Us Sandy Land accounted for 82.7% of the total oasisization area, and the oasisization land in the sandy land was generally stable. Zoning management strategies should be applied according to the stability of sand belt and transformation pattern of oasisization land to achieve the goal of efficient system management and improvement, including eliminating sand hazards at desertification expansion areas with strong wind and sand activities, consolidating sand resources at oasisization areas where ecologically fragile desertification was frequent, and sustainably managing and utilizing sand resources at stable expansion of oases in forest- and grass-rich oasisization areas.

Mechanism of dexmedetomidine protection against cisplatin induced acute kidney injury in rats.

OBJECTIVE: This study explored the molecular mechanisms by which dexmedetomidine (Dex) alleviates cisplatin (CP)-induced acute kidney injury (AKI) in rats. METHODS: CP-induced AKI models were established, and Dex was intraperitoneally injected at different concentrations into rats in the model groups. Subsequently, rats were assigned to the control, CP, CP + Dex 10 µg/kg, and CP + Dex 25 µg/kg groups. After weighing the kidneys of the rats, the kidney arterial resistive index was calculated, and CP-induced AKI was evaluated. In addition, four serum biochemical indices were measured: histopathological damage in rat kidneys was detected; levels of inflammatory factors, interleukin (IL)-1ß, IL-18, IL-6, and tumor necrosis factor alpha, in kidney tissue homogenate of rats were assessed through enzyme-linked immunosorbent assay (ELISA); and levels of NLRP-3, caspase-1, cleaved caspase-1, gasdermin D (GSDMD), and GSDMD-N in kidney tissues of rats were determined via western blotting. RESULTS: Dex treatment reduced nephromegaly and serum clinical marker upregulation caused by CP-induced AKI. In addition, hematoxylin and eosin staining revealed that Dex treatment relieved CP-induced kidney tissue injury in AKI rats. ELISA analyses demonstrated that Dex treatment reduced the upregulated levels of proinflammatory cytokines in the kidney tissue of AKI rats induced by CP, thereby alleviating kidney tissue injury. Western blotting indicated that Dex alleviated CP-induced AKI by inhibiting pyroptosis mediated by NLRP-3 and caspase-1. CONCLUSION: Dex protected rats from CP-induced AKI, and the mechanism may be related to NLRP-3/Caspase-1-mediated pyroptosis.

Salicylaldehyde-Cobalt(II)-Catalyzed C-H Alkoxylation of Indoles with Secondary Alcohols.

A straight and efficient protocol for the synthesis of hindered indole-ethers via C-H alkoxylation of indoles was developed by a cobalt-catalyzed cross-dehydrogenative coupling reaction with secondary alcohols. The selection of the salicylaldehyde-Co(II) catalyst enables the reaction to proceed under conditions without acid or base addition in the presence of limited alcohols. The protocol has broad substrate scope for both indole and secondary alcohols and exhibits good functional tolerance. The synthetic applications are proven by gram-scale reaction and further diversification of the product. Preliminary mechanistic investigations indicate that the activation of C-H bonds is not the rate-determining step of the reaction.

Environmental Toxin Biliatresone-Induced Biliary Atresia-like Abnormal Cilia and Bile Duct Cell Development of Human Liver Organoids.

Biliary atresia (BA) is a poorly understood and devastating obstructive bile duct disease of newborns. Biliatresone, a plant toxin, causes BA-like syndrome in some animals, but its relevance in humans is unknown. To validate the hypothesis that biliatresone exposure is a plausible BA disease mechanism in humans, we treated normal human liver organoids with biliatresone and addressed its adverse effects on organoid development, functions and cellular organization. The control organoids (without biliatresone) were well expanded and much bigger than biliatresone-treated organoids. Expression of the cholangiocyte marker CK19 was reduced, while the hepatocyte marker HFN4A was significantly elevated in biliatresone-treated organoids. ZO-1 (a tight junction marker) immunoreactivity was localized at the apical intercellular junctions in control organoids, while it was markedly reduced in biliatresone-treated organoids. Cytoskeleton F-actin was localized at the apical surface of the control organoids, but it was ectopically expressed at the apical and basal sides in biliatresone-treated organoids. Cholangiocytes of control organoids possess primary cilia and elicit cilia mechanosensory function. The number of ciliated cholangiocytes was reduced, and cilia mechanosensory function was hampered in biliatresone-treated organoids. In conclusion, biliatresone induces morphological and developmental changes in human liver organoids resembling those of our previously reported BA organoids, suggesting that environmental toxins could contribute to BA pathogenesis.

New sesquiterpenoids with neuroprotective effects in vitro and in vivo from the Picrasma chinensis.

Three undescribed sesquiterpenes, designed as pichinenoid A-C (1-3), along with nine known ones (4-12) were isolated from the stems and leaves of Picrasma chinensis. The new isolates including their absolute configurations were elucidated based on extensive spectroscopic methods, single crystal X-ray diffraction, and electronic circular dichroism (ECD) experiments, as well as comparison with literature data. Structurally, compounds 1 and 2 are descending sesquiterpenes, while pichinenoid C (3) is a rare sesquiterpene bearing a 2-methylenebut-3-enoic acid moiety at the C-6 side chain. All the isolated compounds were tested for their neuroprotective effects against the H2O2-induced damage on human neuroblastoma SH-SY5Y cells, and most of them showed moderate neuroprotective activity. Especially, compounds 1, 3-5, and 7 showed a potent neuroprotective effect at 25 or 50 µM. Moreover, the neuroprotective effects of compounds 1 and 4 were tested on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Results of western blot and immunofluorescence indicated that compound 4 significantly counteract the toxicity of MPTP, and reversed the expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and striatum (ST) of the mouse brain. Interestingly, western blot data suggested compound 4 also enhanced B-cell lymphoma-2 (Bcl-2) and heme oxygenase 1 (HO-1) expressions in the brain tissues from MPTP damaged mouse.

Triterpenoids and triterpenoid saponins from Vitex negundo and their anti-inflammatory activities.

Seven undescribed polyoxygenated ursane-type triterpenoids (vitnegundins A-G), three undescribed triterpenoid saponins (vitnegundins H-J), and 17 known ones were isolated from an EtOH extract of the aerial parts of Vitex negundo L. The structures of the undescribed compounds were established by extensive spectroscopic analysis. The absolute configurations of vitnegundins A, B, and E were determined by single-crystal X-ray diffraction data. Vitnegundins B-D are pentacyclic triterpenoids possessing rare cis-fused C/D rings and vitnegundins C-H represent undescribed ursane-type triterpenoids with 12,19-epoxy moiety. In the biological activity assay, vitnegundin A, vitnegundin E, and swinhoeic acid displayed inhibitory effects against LPS-induced NO release in BV-2 microglial cells, with IC50 values of 11.8, 44.2, and 19.6 µM, respectively.

Malignant melanoma located in the ureter and gallbladder: A case report and literature review.

RATIONALE: Melanoma is one of a common cutaneous malignancy. Currently, metastatic malignant melanoma is difficult to be diagnosed through imaging examinations. Furthermore, the incidence of metastatic melanoma affecting the gallbladder and ureter is exceptionally rare. PATIENT CONCERNS: A 54-year-old female was admitted to the hospital with a half-month history of left lower back pain. Correlative examination revealed an occupying lesion in the mid-left ureter and the neck of the gallbladder. DIAGNOSES: The patient was initially diagnosed with gallbladder cancer and left ureteral carcinoma based on imaging. Following 2 operations, immunohistochemical staining confirmed the presence of metastatic melanoma involving both the gallbladder and ureter. INTERVENTION: After multidisciplinary consultation and obtaining consent from the patient and her family, the patient underwent left radical nephroureterectomy, radical cholecystectomy, laparoscopic partial hepatectomy (Hep IV, Hep V), and lymph node dissection of hepatoduodenal ligament. OUTCOMES: One month after treatment, the patient imaging showed no disease progression, and at 6 months of follow-up, the patient was still alive. LESSONS: It is difficult to distinguish metastatic melanoma from carcinoma in situ by imaging. In addition, metastatic malignant melanoma lacks specific clinical manifestations and is prone to misdiagnosis, which emphasizes the highly aggressive nature of malignant melanoma.

Fluorescence theranostic PROTACs for real-time visualization of ERα degradation.

Proteolysis targeting chimera (PROTAC) technology, a groundbreaking strategy for degradation of pathogenic proteins by hijacking of the ubiquitin-proteasome-system has become a promising strategy in drug design. However, the real-time monitoring and visualization of protein degradation processes have been long-standing challenges in the realm of drug development. In this research, we sought to amalgamate the highly efficient protein-degrading capabilities of PROTAC technology with the visualization attributes of fluorescent probes, with the potential to pave the path for the design and development of a novel class of visual PROTACs. These novel PROTACs uniquely possess both fluorescence imaging and therapeutic characteristics, all with the goal of enabling real-time observations of protein degradation processes. Our approach involved the utilization of a high ER-targeting fluorescent probe, previously reported in our laboratory, which served as a warhead that specifically binds to the protein of interest (POI). Additionally, a VHL ligand for recruiting E3 ligase and linkers of various lengths were incorporated to synthesize a series of novel ER-inherent fluorescence PROTACs. Among them, compound A3 demonstrated remarkable efficiency in degrading ERα proteins (DC50 = 0.12 µM) and displaying exceptional anti-proliferative activity against MCF-7 cells (IC50 = 0.051 µM). Furthermore, it exhibited impressive fluorescence imaging performance, boasting an emission wavelength of up to 582 nm, a Stokes shift of 116 nm, and consistent optical properties. These attributes make it especially suitable for the real-time, in situ tracking of ERα protein degradation processes, thus may serve as a privileged visual theranostic PROTAC for ERα+ breast cancer. This study not only broadens the application spectrum of PROTAC technology but also introduces a novel approach for real-time visualization of protein degradation processes, ultimately enhancing the diagnostic and treatment efficacy of PROTACs.

Novel estrogen receptor ß/histone deacetylase dual-targeted near-infrared fluorescent probes as theranostic agents for imaging and treatment of prostate cancer.

Estrogen receptor (ER) ß and histone deacetylases (HDACs), when overexpressed, are associated closely with the occurrence and development of prostate cancer and are, therefore, considered important targets and biomarkers used in the clinical treatment of prostate cancer. The present study involved the design and synthesis of the first ERß and HDAC dual-target near-infrared fluorescent probe with both imaging capacity and antitumor activity for prostate cancer. Both P1 and P2 probes exhibited excellent ERß selectivity, with P1 being almost exclusively selective for ERß compared to ERα. In addition, P1 exhibited good optical properties, such as strong near-infrared emission, large Stokes shift, and better anti-interference ability, along with excellent imaging ability for living cells. P1 also exhibited potent inhibitory activity against HDAC6 and DU-145 cells, with IC50 values of 52 nM and 0.96 µM, respectively. Further, P1 was applied successfully for the in vivo imaging of prostate cancer in a mouse model, and significant in vivo antitumor efficacy was achieved. The developed dual-target NIR fluorescent probe is expected to serve as an effective tool in the research on prostate cancer, leading to novel insights for the theranostic study of diseases related to ERß and HDACs.

A computed tomography urography-based machine learning model for predicting preoperative pathological grade of upper urinary tract urothelial carcinoma.

OBJECTIVES: Development and validation of a computed tomography urography (CTU)-based machine learning (ML) model for prediction of preoperative pathology grade of upper urinary tract urothelial carcinoma (UTUC). METHODS: A total of 140 patients with UTUC who underwent CTU examination from January 2017 to August 2023 were retrospectively enrolled. Tumor lesions on the unenhanced, medullary, and excretory periods of CTU were used to extract Features, respectively. Feature selection was screened by the Pearson and Spearman correlation analysis, least absolute shrinkage and selection operator algorithm, random forest (RF), support vector machine (SVM), and eXtreme Gradient Boosting (XGBoost). The logistic regression (LR) was used to screen for independent influencing factors of clinical baseline characteristics. Machine learning models based on different feature datasets were constructed and validated using algorithms such as LR, RF, SVM, and XGBoost. By computing the selected features, a radiomics score was generated, and a diverse feature dataset was constructed. Based on the training set, 16 ML models were created, and their performance was evaluated using the validation set for metrics including sensitivity, specificity, accuracy, area under the receiver operating characteristic curve (AUC), and others. RESULTS: The training set consisted of 98 patients (mean age: 64.5 ± 10.5 years; 30 males), whereas the validation set consisted of 42 patients (mean age: 65.3 ± 9.78 years; 17 males). Hydronephrosis was the best independent influence factor (p < 0.05). The RF model had the best performance in predicting high-grade UTUC, with AUC of 0.914 (95% Confidence Interval [95%CI] 0.852-0.977) and 0.903 (95%CI 0.809-0.997) in the training set and validation set, and accuracy of 0.878 and 0.857, respectively. CONCLUSIONS: An ML model based on the RF algorithm exhibits excellent predictive performance, offering a non-invasive approach for predicting preoperative high-grade UTUC.

Clinical algorithm model based on cfDNA to predict SLE disease activity.

BACKGROUND: Circulating cell-free DNA (cfDNA) has been widely used as a new liquid-biopsy marker. Dysregulation of cfDNA has been found in patients with systemic lupus erythematosus (SLE). However, the detailed association between cfDNA and SLE has not been thoroughly studied. METHODS: Plasma samples were collected from 88 patients with active SLE and 39 patients with inactive SLE. The cfDNA concentration was determined, and the length and distribution of cfDNA fragments were verified. RESULTS: cfDNA concentrations were significantly higher in patients with active SLE than in patients with inactive SLE (0.4 [0.18-0.897] ng/µL vs 0.249 [0.144-0.431] ng/µL; p = .043). cfDNA fragments were enriched in the ranges of 153-198 bp and 300-599 bp. cfDNA concentrations were associated with the reduction of the anti-double-stranded DNA (dsDNA) antibodies titer (r = -0.301, p = .034). The presence of anti-U1 ribonucleoprotein (p = .012), anti-Sjogren syndrome A (p = .024), anti-dsDNA (p = .0208), and anti-nucleosome antibodies (p = .0382) might associate to the variation of cfDNA concentration. Reduced cfDNA concentration was associated with renal damage in active SLE patients (0.31 [0.11-0.73] ng/µL vs 0.65 [0.27-1.53] ng/µL; p = .009). The Active index, a combination model including cfDNA concentration and other clinical indices, had an area of 0.886 under the receiver operating characteristics curve for distinguishing active SLE. The Active index was positively correlated with the SLE disease activity index score (r = 0.6724, p < .0001). CONCLUSIONS: Through systematic stratified analysis and clinical algorithm model, this study found that plasma cfDNA concentration is closely related to SLE disease severity, which has guiding significance for the future clinical application of cfDNA in SLE.

Clerodane diterpenoids with in-vitro anti-neuroinflammatory activity from the tuberous root of Tinospora sagittata (Menispermaceae).

Twenty-six clerodane diterpenoids have been isolated from T. sagittata, a plant species of traditional Chinese medicine Radix Tinosporae, also named as "Jin Guo Lan". Among them, there are eight previously undescribed clerodane diterpenoids (tinotanoids A-H: 1-8), and 18 known diterpenoids (9-26). The absolute configurations of compounds 1, 2, 5, 8, 13, 17 and 20 were determined by single-crystal X-ray diffraction. Compound 1 is the first example of rotameric clerodane diterpenoid with a γ-lactone ring which is constructed between C-11 and C-17; meanwhile, compounds 3 and 4 are two pairs of inseparable epimers. Compounds 2, 12 and 17 demonstrated excellent inhibitory activity on NO production against LPS-stimulated BV-2 cells with IC50 values of 9.56 ± 0.69, 9.11 ± 0.53 and 11.12 ± 0.70 µM, respectively. These activities were significantly higher than that of the positive control minocycline (IC50 = 23.57 ± 0.92 µM). Moreover, compounds 2, 12 and 17 dramatically reduced the LPS-induced upregulation of iNOS and COX-2 expression. Compounds 2 and 12 significantly inhibited the levels of pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 that were increased by LPS stimulation.