Single-cell transcriptomics reveal potent extrafollicular B cell response linked with granzyme K+ CD8 T cell activation in lupus kidney.

OBJECTIVES: B and T cells constitute the majority of infiltrating lymphocytes in the kidney and represent the local perpetrators in lupus nephritis (LN), but the underlying pathogenic mechanisms are not well elucidated. The aim of this study is to explore the kidney-specific adaptive immune landscape in patients with active LN at the single-cell level. METHODS: We performed single-cell RNA/B cell receptor (BCR)/T cell receptor (TCR) sequencing analysis on sorting-purified B and T cells from the kidney and paired peripheral blood of patients with active LN, and the periphery of matched controls. Flow cytometry, Assay for Transposase Accessible-sequencing, multiplexed immunohistochemistry and functional studies were performed to validate the transcriptomic results. RESULTS: High infiltrations of intrarenal atypical B cells (ABCs) and antibody-secreting cells (ASCs) were identified in the B cell compartment. The single-cell BCR repertoire analysis revealed strong clonal expansion of intrarenal ASCs dominated by IGHG1 and IGHG3 isotypes, accompanied by lower frequencies of heavy-chain and light-chain somatic mutations, compared with the peripheral ASCs. Notably, a unique expansion of IGHG4-59 and clonal overlap between ABCs and ASCs was found in kidney-specific clonotypes. In the T cell compartment, we identified granzyme K (GZMK)+ CD8 T cells as the dominant kidney-associated T cells which shared inflammation- and stress-related gene pathways with ABCs. Intrarenal GZMK+ CD8 T cells highly expressed IFNG and displayed strong communication with ABCs via the type II interferon (IFN) pathway. Intrarenal GZMK+ CD8 T cells and ABCs were largely co-localised within the tertiary lymphoid structure, and GZMK+ CD8 T cells potentially contributed to the differentiation of ABCs via IFN-γ and interleukin-21. CONCLUSIONS: Our study revealed a potent extrafollicular B cell response linked with overactivation of GZMK+ CD8 T cells in the kidney of patients with LN, which may lead to innovative treatments for LN.

Determining the maximum tolerated dose of paclitaxel combined with fixed dose of cisplatin for hyperthermic intraperitoneal chemotherapy in ovarian cancer: A multicenter phase I trial.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of paclitaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered via hyperthermic intraperitoneal chemotherapy (HIPEC) to patients with ovarian cancer. METHODS: This multicenter Phase I trial employed a Bayesian Optimal Interval (BOIN) design. The MTD was determined to have a target dose-limiting toxicity (DLT) rate of 25%. The starting dose was 175 mg/m2. The Data and Safety Monitoring Board made decisions regarding dose escalation or de-escalation in increments of 25 mg/m2 for subsequent patient cohorts, up to a maximum sample size of 30 or 12 patients treated at a given dose. RESULTS: Twenty-one patients participated in this study. Among the three evaluable patients who received 150 mg/m2 paclitaxel, no DLTs were observed. Among the 12 evaluable patients who received 175 mg/m2 paclitaxel, two reported DLTs: one had grade 4 neutropenia and one had grade 4 anemia, neutropenia, and leukopenia. Four of the six evaluable patients who received 200 mg/m2 paclitaxel reported DLTs: one patient had grade 4 diarrhea, one had grade 3 kidney injury, and two had grade 4 anemia. The isotonic estimate of the DLT rate in the 175 mg/m2 dose group was 0.17 (95% confidence interval, 0.02-0.42), and this dose was selected as the MTD. CONCLUSION: Paclitaxel, when combined with a fixed dose of cisplatin (75 mg/m2), can be safely administered intraperitoneally at a dose of 175 mg/m2 in patients with ovarian cancer who received HIPEC (43 °C, 90 min) following cytoreductive surgery.

The Impact of Kidney/Pancreas Transplantation on Peripheral Arterial Disease.

INTRODUCTION: It is unclear whether kidney/pancreas (KP) transplantation will prevent the progression of peripheral arterial disease (PAD) in patients with insulin dependent diabetes (IDDM) and end-stage renal disease. We sought to determine the pre- and posttransplant prevalence of symptomatic PAD and changes in carotid artery intima-media thickness (IMT) in KP recipients. METHODS: In this single center study, outcomes were compared between KP recipients with and without a history of PAD. A subset of recipients underwent pre- and posttransplant IMT measurements. RESULTS: Among the study group (N = 107), 18 (17%) recipients admitted to a pretransplant history of symptomatic PAD, comprised 11 foot infections and 7 amputations (5 minor and 2 major). Baseline characteristics of age, gender, race, years of diabetes, dialysis history, smoking history, years of hypertension, and history of coronary artery disease (CAD) were equivalent between PAD and non-PAD cohorts. At a median follow-up of 60 months (IQR: 28, 110), 16 (15%) KP recipients had suffered a PAD event. In multivariate analysis, a pretransplant history of PAD (hazard ratio [HR] 9.66, p < 0.001) and CAD (HR 3.33, p = 0.04) were independent predictors of posttransplant PAD events. Among a subset of 20 recipients (3 with PAD), mean IMT measurements pretransplant and at a median of 24 (range 18-24) months posttransplant, showed no evidence of disease progression. CONCLUSION: Based on IMT measurements and clinical results, KP transplantation stabilized PAD in most patients, but did not alter outcomes of symptomatic PAD recipients. A pretransplant history of PAD and CAD was an independent predictor of posttransplant PAD events.

Discovery and Bioinspired Synthesis of Salpratone A.

Salpratone A (1), a novel abietane diterpenoid containing a unique cis-fused A/B ring, was isolated from Salvia prattii. Bioactivity studies showed that 1 has potent activity in inhibiting platelet aggregation induced by multiple agonists as well as antithrombotic efficacy in the FeCl3-induced rat in vivo thrombosis model. Furthermore, a bioinspired synthesis of 1 from the abundant natural product ferruginol was achieved in 6 steps with a 22% overall yield. The key steps include a stereoselective allyl oxidation and a subsequent regioselective Meinwald rearrangement.

Anti-inflammatory bicyclic polyprenylated acylphloroglucinols with diverse architectures including an unprecedented 6/6/6 tricyclic core from Garcinia yunnanensis.

Garciyunnanol A (1), an unprecedented 1,2-seco-bicyclic polyprenylated acylphloroglucinol (BPAP) possessing a unique 6/6/6 tricyclic core, was characterized from Garcinia yunnanensis together with 16 BPAPs, including eight new compounds (garciyunnanols B-I, 2-9). Biogenetically, the bicyclo[3.3.1]nonane-2,4,9-trione moiety of 12 reconstructed the bicyclic δ-lactone core of 2 through Norrish type Ⅰ cleavage and cyclization, followed by a cyclization of two side chains to form an intriguing 6/6/6 tricyclic core of 1. Their structures were elucidated through analysis of spectroscopic data, calculation and comparison of ECD spectra. Bioactivity evaluation manifested that compounds 1, 2, 5, 6 and 14 demonstrated superior inhibition of NO production compared to the positive control dexamethasone. Notably, compound 5 exhibited a dose-dependent inhibitory effect on NO production, with an IC50 value of 0.25 ± 0.87 µM. Furthermore, experiments involving ELISA, Western blotting, and immunofluorescence staining revealed that 5 effectively reduced the secretion of interleukin-1ß in LPS plus nigericin-stimulated THP-1 macrophages by inhibiting the activation of the NLRP3 inflammasome.

Discovery of a selective TRF2 inhibitor FKB04 induced telomere shortening and senescence in liver cancer cells.

Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.

Neuromechanisms of simulation-based arthroscopic skills assessment: a fNIRS study.

BACKGROUND: The neural mechanisms underlying differences in the performance of simulated arthroscopic skills across various skill levels remain unclear. Our primary objective is to investigate the learning mechanisms of simulated arthroscopic skills using functional near-infrared spectroscopy (fNIRS). METHODS: We recruited 27 participants, divided into three groups: novices (n = 9), intermediates (n = 9), and experts (n = 9). Participants completed seven arthroscopic tasks on a simulator, including diagnostic navigation, triangulation, grasping stars, diagnostic exploration, meniscectomy, synovial membrane cleaning, and loose body removal. All tasks were videotaped and assessed via the simulator system and the Arthroscopic Surgical Skill Evaluation Tool (ASSET), while cortical activation data were collected using fNIRS. Simulator scores and ASSET scores were analyzed to identify different level of performance of all participants. Brain region activation and functional connectivity (FC) of different types of participants were analyzed from fNIRS data. RESULTS: Both the expert and intermediate groups scored significantly higher than the novice group (p < 0.001). There were significant differences in ASSET scores between experts and intermediates, experts and novices, and intermediates and novices (p = 0.0047, p < 0.0001, p < 0.0001), with the trend being experts > intermediates > novices. The intermediate group exhibited significantly greater activation in the left primary motor cortex (LPMC) and left prefrontal cortex (LPFC) compared to the novice group (p = 0.0152, p = 0.0021). Compared to experts, the intermediate group demonstrated significantly increased FC between the presupplementary motor area (preSMA) and the right prefrontal cortex (RPFC; p < 0.001). Additionally, the intermediate group showed significantly increased FC between the preSMA and LPFC, RPFC and LPFC, and LPMC and LPFC compared to novices (p = 0.0077, p = 0.0285, p = 0.0446). CONCLUSION: Cortical activation and functional connectivity reveal varying levels of activation intensity in the PFC, PMC, and preSMA among novices, intermediates, and experts. The intermediate group exhibited the highest activation intensity.

Thermosensitive hydrogel with emodin-loaded triple-targeted nanoparticles for a rectal drug delivery system in the treatment of chronic non-bacterial prostatitis.

BACKGROUND: The complex etiology and pathogenesis underlying Chronic Non-Bacterial Prostatitis (CNP), coupled with the existence of a Blood Prostate Barrier (BPB), contribute to a lack of specificity and poor penetration of most drugs. Emodin (EMO), a potential natural compound for CNP treatment, exhibits commendable anti-inflammatory, anti-oxidant, and anti-fibrosis properties but suffers from the same problems as other drugs. METHODS: By exploiting the recognition properties of lactoferrin (LF) receptors that target intestinal epithelial cells (NCM-460) and prostate epithelial cells (RWPE-1), a pathway is established for the transrectal absorption of EMO to effectively reach the prostate. Additionally, hyaluronic acid (HA) is employed, recognizing CD44 receptors which target macrophages within the inflamed prostate. This interaction facilitates the intraprostatic delivery of EMO, leading to its pronounced anti-inflammatory effects. A thermosensitive hydrogel (CS-Gel) prepared from chitosan (CS) and ß-glycerophosphate disodium salt (ß-GP) was used for rectal drug delivery with strong adhesion to achieve effective drug retention and sustained slow release. Thus, we developed a triple-targeted nanoparticle (NPs)/thermosensitive hydrogel (Gel) rectal drug delivery system. In this process, LF, with its positive charge, was utilized to load EMO through dialysis, producing LF@EMO-NPs. Subsequently, HA was employed to encapsulate EMO-loaded LF nanoparticles via electrostatic adsorption, yielding HA/LF@EMO-NPs. Finally, HA/LF@EMO-NPs lyophilized powder was added to CS-Gel (HA/LF@EMO-NPs Gel). RESULTS: Cellular assays indicated that NCM-460 and RWPE-1 cells showed high uptake of both LF@EMO-NPs and HA/LF@EMO-NPs, while Raw 264.7 cells exhibited substantial uptake of HA/LF@EMO-NPs. For LPS-induced Raw 264.7 cells, HA/LF@EMO-NPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways. Tissue imaging corroborated the capacity of HA/LF-modified formulations to breach the BPB, accumulating within the gland's lumen. Animal experiments showed that rectal administration of HA/LF@EMO-NPs Gel significantly reduced inflammatory cytokine expression, oxidative stress levels and fibrosis in the CNP rats, in addition to exerting anti-inflammatory effects by inhibiting the NF-κB signaling pathway without obvious toxicity. CONCLUSION: This triple-targeted NPs/Gel rectal delivery system with slow-release anti-inflammatory, anti-oxidant, and anti-fibrosis properties shows great potential for the effective treatment of CNP.

Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis.

CUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered that compound 27 disrupted CELF1-RNA binding via structure-based virtual screening and biochemical assays. Compound 27 binds directly to CELF1 and competes with RNA for binding to CELF1. Compound 27 promotes IFN-γ secretion and suppresses TGF-ß1-induced hepatic stellate cell (HSC) activation by inhibiting CELF1-mediated IFN-γ mRNA decay. In vivo, compound 27 attenuates CCl4-induced murine liver fibrosis. Furthermore, the structure-activity relationship analysis was performed and compound 841, a derivative of compound 27, was identified as a selective CELF1 inhibitor. In conclusion, targeting CELF1 RNA-binding activity with small molecules was achieved, which provides a novel strategy for treating liver fibrosis and other CELF1-mediated diseases.

Efficacy and safety of tetrandrine in treatment of rheumatoid arthritis: a meta-analysis. / æ±‰é˜²å·±ç”²ç´ æ²»ç–—ç±»é£Žæ¹¿å ³èŠ‚ç‚Žæœ‰æ•ˆæ€§å’Œå®‰å ¨æ€§çš„meta分析.

OBJECTIVES: To explore the efficacy and safety of tetrandrine in the treatment of rheumatoid arthritis. METHODS: Randomized controlled studies of tetrandrine in the treatment of rheumatoid arthritis were searched in CNKI, VIP, Wanfang database, SinoMed, PubMed, Springer, Web of Science and Cochrane Central Register of Controlled Trails databases. A meta-analysis was conducted using R 3.5.3 software to evaluate the clinical outcomes, including the total effective rate, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), visual analogue scale (VAS), disease activity score (DAS), tender joint count (TJC), swollen joint count (SJC), and morning stiffness duration, as well as adverse events of rheumatoid arthritis patients. RESULTS: A total of 10 articles were included in the study. The meta-analysis indicated that tetrandrine significantly improved the total effective rate (OR=3.27, 95%CI: 2.01-5.37, P<0.01), ESR (SMD=1.12, 95%CI: 0.06-2.19, P<0.05), CRP (SMD=0.75, 95%CI: 0.28-1.22, P<0.01), VAS (SMD=0.64, 95%CI: 0.29-1.00, P<0.01), TJC (SMD=1.16, 95%CI: 0.58-1.74, P<0.01), SJC (SMD=0.85, 95%CI: 0.40-1.31, P<0.01), and morning stiffness (SMD=1.09, 95%CI: 0.68-1.50, P<0.01). However, no statistical significance was found in RF (SMD=1.70, 95%CI: －1.10-4.51, P>0.05) and DAS (SMD=0.26, 95%CI: －0.59-1.11, P>0.05). The overall incidence of adverse events associated with tetrandrine treatment for rheumatoid arthritis was 20% (95%CI: 12%-27%, I2=60%, P<0.05), with mild severity and favorable outcomes. CONCLUSIONS: Tetrandrine is effective in the treatment of RA patients with a mild degree of adverse events.

Real-world experience of postoperative adjuvant chemoimmunotherapy in patients with perihilar cholangiocarcinoma at high risk of recurrence.

BACKGROUND: This study aimed to assess whether postoperative adjuvant chemoimmunotherapy could lead to better clinical outcomes for high-risk patients with perihilar cholangiocarcinoma (pCCA). METHODS: In the cohort study, we retrospectively reviewed patients who received surgical resection for pCCA with curative intent from January 2018 to December 2021 at the Sun Yat-sen Memorial Hospital. The patients at high risk for relapse were further analyzed. Among them, 20 patients received adjuvant chemoimmunotherapy, 28 patients received adjuvant chemotherapy, and 33 patients received surgery alone. The oncological outcomes and drug-associated adverse events were evaluated. RESULTS: The 2-year overall survival (OS) rates in patients treated with adjuvant chemoimmunotherapy, adjuvant chemotherapy, and surgery alone were 80.0%, 49.4% and 22.6%, respectively. Univariable and multivariable Cox analyses showed that the treatment regimen and TNM stage were associated with adverse OS. Adjuvant chemoimmunotherapy led to an increase in OS compared with adjuvant chemotherapy [hazard ratio (HR) = 3.253; 95% confidence interval (CI) 1.072-9.870; P = 0.037] or surgery alone (HR = 7.560; 95% CI 2.508-22.785; P < 0.001). The median recurrence-free survival was 22.0 months for the adjuvant chemoimmunotherapy group, 17.0 months for the adjuvant chemotherapy group, and 13.2 months for the surgery alone group (P = 0.177); these differences were not significant. The chemoimmunotherapy group was associated with more frequent hematological side effects than the chemotherapy group, but the difference was not statistically significant. CONCLUSION: Postoperative adjuvant chemoimmunotherapy for resected pCCA patients showed improved OS compared with adjuvant chemotherapy or surgery alone, and further prospectively randomized controlled trials are necessary to validate these results.

Boosting Activity and Selectivity of UiO-66 through Acidity/Alkalinity Functionalization in Dimethyl Carbonate Catalysis.

The acid-base properties of supports have an enormous impact on catalytic reactions to regulate the selectivity and activity of supported catalysts. Herein, a train of Pd-X-UiO-66 (X = NO2 , NH2 , and CH3 ) catalysts with different acidity/alkalinity functional groups and encapsulated Pd(II) species is first developed, whose activities in dimethyl carbonate (DMC) catalysis are then investigated in details. Thereinto, the Pd-NO2 -UiO-66 catalyst with acidity functionalization exhibits the best catalytic behavior: the DMC selectivity stemmed from methyl nitrite (MN) is up to 68%, the conversion of CO is 73.4%. The obtained experimental results demonstrate that the NO2 group not only affected the interaction between X-UiO-66 and Pd(II) active sites but also play an indispensable role in the adsorption and activation of MN and CO, which remarkably promote the formation of the COOCH3 * intermediate and DMC product.

The central helicase domain holds the major conformational epitopes of melanoma differentiation-associated gene 5 autoantibodies.

OBJECTIVES: Autoantibodies against MDA5 serve as a biomarker for dermatomyositis (DM) and a risk factor for interstitial lung disease (ILD). MDA5 is a protein responsible for sensing RNA virus infection and activating signalling pathways against it. However, little is known about antigen epitopes on MDA5 autoantibodies. We aimed to determine the interaction of the MDA5 autoantibody-antigen epitope. METHODS: Cell-based assays (CBAs), immunoprecipitation-immunoblot assays, and various immunoblotting techniques were used in the study. RESULTS: We demonstrate that DM patient autoantibodies recognize MDA5 epitopes in a native conformation-dependent manner. Furthermore, we identified the central helicase domain formed by Hel1, Hel2i, Hel2, and pincer (3Hel) as the major epitopes. As proof of principle, the purified 3Hel efficiently absorbed MDA5 autoantibodies from patient sera through immunoprecipitation-immunoblot assay. CONCLUSION: Our study uncovers the nature of antigen epitopes on MDA5 and provides guidance for diagnosis and targeted therapeutic approach development.

Longitudinal study of patients with antimelanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease.

OBJECTIVES: To describe the 8-year longitudinal study and long-term prognosis of a large inception cohort of anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (MDA5+) DM-interstitial lung disease (ILD) patients. METHODS: In total, 216 patients diagnosed with MDA5+ DM-ILD were enrolled and followed up to analyse long-term survival rate. Demographic and clinical variables were collected at baseline and each temporal end point. Seventy patients who survived the first year were analysed for the long-term serological and respiratory outcomes. RESULTS: A total of 85 patients (39.3%) died during the follow-up period up to 96 months, with 89% of the deaths occurring in the first year after diagnosis. Long-term outcome was reported in 70 patients. Serological markers including anti-MDA5 antibody showed significant improvement with time. Radiographic findings and pulmonary function also improved notably in the follow-up period, especially in rapidly progressive ILD group, as measured by high-resolution computed tomography imaging scores, the estimated forced vital capacity, estimated diffusing capacity of lung carbon monoxide and dyspnoea scores. Early application of anti-fibrosis therapy helped to improve long-term pulmonary function. CONCLUSIONS: MDA5+ DM-ILD patients had a high mortality rate despite aggressive treatment. Patients who survived the first year usually showed a significant improvement in serological markers and pulmonary function during the long-term follow-up.

Metabolomics integrated network pharmacology reveals the mechanism of Ma-Mu-Ran Antidiarrheal Capsules on acute enteritis mice.

Acute enteritis (AE) is a type of digestive disease caused by biochemical factors that irritate the intestinal tract or pathogenic bacteria that infect it. In China, Ma-Mu-Ran Antidiarrheal Capsules (MMRAC) have been applied against diarrhea caused by AE and bacillary dysentery for many years, but the underlying mechanisms of their beneficial effects are not known. In the present study, network pharmacology and metabolomics were performed to clarify the active ingredients of MMRAC and explore the specific mechanism of MMRAC on AE mice. A total of 43 active components of MMRAC with 87 anti-AE target genes were identified, and these target genes were enriched in IL-17 and HIF-1 signaling pathways. Integration analysis revealed that purine metabolism was the critical metabolic pathway by which MMRAC exerted its therapeutic effect against AE. Specifically, MAPK14, MMP9, PTGS2, HIF1A, EGLN1, NOS2 were the pivotal targets of MMRAC for the treatment of AE, and Western blot analysis revealed MMRAC to decrease protein levels of these pro-inflammatory signaling molecules. According to molecular docking, these key targets have a strong affinity with the MMRAC compounds. Collectively, MMRAC relieved the colon inflammation of AE mice via regulating inflammatory signaling pathways to reduce hypoxia and improved energy metabolism.

Age-dependent interaction between Life's Essential 8 and chronic kidney disease: A national cross-sectional analysis.

OBJECTIVE: Chronic kidney disease (CKD), an age-related condition, is closely associated with cardiovascular disease. We aimed to examine the age-dependent interaction between Life's Essential 8 (LE8), the updated measurement of cardiovascular health (CVH), and CKD in the United States. METHODS: The cross-sectional study involved 25,529 participants from National Health and Nutrition Examination Survey in 2007-2018. Multivariate logistic regressions were used to estimate the age-dependent interaction between LE8 and CKD, and restricted cubic spline regressions were used to analyze the dose-response relationships between LE8 and CKD among adults and all age subgroups. RESULTS: Overall, 2934 (9.3%), 17,278 (66.2%), and 5317 (24.5%) participants had low, moderate, and high CVH, separately. After adjusting for the potential covariates, LE8 was negatively associated with CKD [odds ratio (OR) for per 1 standard deviation (SD) increase and 95%CI, 0.71 (0.67, 0.75)], with a nonlinear dose-response relationship (P for nonlinearity = 0.001). The inversed association was stronger among participants aged 65 and older (0.65 (0.59, 0.71)) compared to youngers [20-39 years, 0.63 (0.59, 0.58), 40-64 years, 0.63 (0.59, 0.58)] (P for interaction = 0.002). CONCLUSIONS: CVH, as measured by the LE8 score, was negatively associated with the presence of CKD in non-linear fashions, more pronounced in participants aged 65 and older compared to younger age groups.

Research progress of good markers for canine mammary carcinoma.

PURPOSE: Mammary gland tumors are the most common neoplastic diseases in elderly female dogs, about 50% of which are considered to be malignant. Canine mammary tumors are similar to human breast cancers in many respects, so canine mammary tumors are frequently studied alongside human breast cancer. This article mentioned KI-67, HER-2, COX-2, BRCA1, BRCA2, P53, CA15-3, MicroRNA, Top2α and so on. All these markers are expected to have an important role in the clinic. METHODS: Existing markers of canine mammary carcinoma are reviewed, and the expression of each marker and its diagnostic role for this tumor are described in detail. RESULTS: This article introduced several effective markers of canine mammary tumors, among them, antigen KI-67 (KI-67), human epidermal growth factor receptor 2 (HER-2), cyclooxygenase 2 (COX-2) are promising and can be detected in both serum and tissue samples. Breast cancer caused by mutations in the breast cancer 1 gene (BRCA1) and breast cancer 2 gene (BRCA2) is also a hot topic of research. In addition to the above symbols, tumor protein p53 (p53), cancer antigen15-3 (CA15-3), MicroRNA (miRNA), topoisomerase πα (Top2α), proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGFR) and E-cadherin will also be involved in this paper. We will also mention Mammaglobin, which has been rarely reported so far.

Structurally Diverse Cytotoxic Polyphenols from Garcinia gracilis.

Thirty-five diverse polyphenols, belonging to seven structure classes, were isolated from Garcinia gracilis, a medicinal and edible plant sampled from Laos. The structures of nine new compounds, gargarcilones A-I (1-3, 5-7, 10, 12, and 17), were established using spectroscopic, X-ray diffraction, and experimental and calculated ECD methods. Additionally, we revised the stereochemical assignment of cochinchinoxanthone and cochinchinoxanthone C. The compounds were evaluated for antiproliferative activity against five human tumor cell lines (HL-60, A549, SMMC-7721, MDA-MB-231, and SW480). Compounds 1-4, 7, and 8 exhibited cytotoxic activity with IC50 values of 0.5-8.9 µM. Compound 3 significantly induced apoptosis in SMMC-7721 cells.

11,12-seco-Abietane-type diterpene lactones with potential antiplatelet activity from Salvia prattii.

Eleven new abietane-type diterpene lactones, salpratlactones D-N (1-11), including five 11,12-seco-11-nor-abietane diterpenes (1-5), four 11,12-seco-abietane diterpenes (6-9), two 20(10 â†’ 5)-abeo-4,5;11,12-bis-seco-abietane diterpenes (10-11), and two known analogues (12-13), were characterized from Salvia prattii. Notably, compounds 1-3 were characterized by a unique linear 6/6/6 tricyclic skeleton. The structures were established by spectroscopic data interpretation, calculated NMR-DP4+ and electronic circular dichroism analysis, as well as single-crystal X-ray diffraction. A bioactivity study showed that 1, 2, 5, 11, and 12 can potently inhibit platelet aggregation induced by arachidonic acid (AA), with IC50 values of 5.66-16.10 µg/ml, stronger than aspirin. In addition, the lactate dehydrogenase assay showed that they had no effect on platelet integrity. Structurally, the same 1,2-benzopyrone fragments of 1, 2, and 5 should be the important pharmacophore for antiplatelet activity.

Recent advance in phytonanomedicine and mineral nanomedicine delivery system of the treatment for acute myeloid leukemia.

Acute myeloid leukemia (AML) is an invasive hematopoietic malignancy caused by excessive proliferation of myeloblasts. Classical chemotherapies and cell transplantation therapies have remarkable efficacy in AML treatment; however, 30-40% of patients relapsed or had refractory disease. The resistance of AML is closely related to its inherent cytogenetics or various gene mutations. Recently, phytonanomedicine are found to be effective against resistant AML cells and have become a research focus for nanotechnology development to improve their properties, such as increasing solubility, improving absorption, enhancing bioavailability, and maintaining sustained release and targeting. These novel phytonanomedicine and mineral nanomedicine, including nanocrystals, nanoemulsion, nanoparticles, nanoliposome, and nanomicelles, offer many advantages, such as flexible dosages or forms, multiple routes of administration, and curative effects. Therefore, we reviewed the application and progress of phytomedicine in AML treatment and discussed the limitations and future prospects. This review may provide a solid reference to guide future research on AML treatment.