A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT.

The tumor suppressor protein p53 is central to cancer biology, with its pathway reactivation emerging as a promising therapeutic strategy in oncology. This study introduced LZ22, a novel compound that selectively inhibits the growth, migration, and metastasis of tumor cells expressing wild-type p53, demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant p53. LZ22's mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 protein. This interaction disrupted the MDM2-p53 binding, consequently stabilizing p53 by shielding it from proteasomal degradation. LZ22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling pathway. Moreover, LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT, effectively reducing tumor cell migration and distal metastasis. Importantly, LZ22 administration in tumor-bearing mice did not manifest notable side effects. The findings position LZ22 as a structurally unique reactivator of p53, offering therapeutic promise for the management of human cancers with wild-type TP53.

Anti-psoriasis molecular targets and active components discovery of Optimized Yinxieling Formula via affinity-purified strategy.

Psoriasis, a prevalent inherited skin condition, involves an inflammatory response as a key pathogenic mechanism. The Optimized Yinxieling Formula (OYF), rooted in traditional Chinese medicine, is extensively utilized in clinical settings to treat psoriasis. Although previous studies have demonstrated OYF's significant anti-inflammatory effects in psoriasis, its potential molecular targets and active components remain unexplored. This study aimed to unveil the anti-psoriasis molecular targets and active components of OYF. Our findings indicated that OYF extract markedly reduced the production of several inflammatory mediators, including IL-23, nitric oxide, TNF-α, and IL-1ß, in LPS-induced RAW264.7 cells. We synthesized OYF extract-crosslinked beads to isolate pharmacological targets from RAW264.7 lysates using an affinity purification strategy, known as Target Fishing. The enriched target proteins were subsequently identified via LC-MS/MS, followed by bioinformatics analysis to map the psoriasis-associated pathway-gene network. We identified a total of 76 potential target proteins, which were highly associated with mRNA transcription mechanisms. In particular, pathway-gene network analysis revealed that the IL-23 inflammatory pathway was involved in the anti-psoriasis effect of OYF extract. We further utilized a target protein-based affinity capture strategy, combined with LC-MS and SPR analysis, to globally screen OYF's active components, focusing on the mRNA transcription regulator, fused in sarcoma (FUS). This process led to the identification of umbelliferone, vanillic acid, protocatechuic acid, gentisic acid, and echinacoside as key compounds targeting FUS to inhibit IL-23 expression. Additionally, we formulated a compound cocktail (CpdC), which significantly reduced psoriasis area and severity index (PASI) scores and the expressions of IL-23 and Ki67 in an imiquimod (IMQ)-induced psoriasis mouse model. Collectively, our study elucidates the primary molecular targets and active components of OYF, offering novel insights for psoriasis treatment.

Real-world effects of Yishen Tongbi decoction for rheumatoid arthritis: protocol for a prospective, observational, multicenter cohort study with validation against double-blind, randomized, controlled trial.

Introduction: Rheumatoid arthritis (RA) is a globally challenging and refractory autoimmune disease, constituting a serious menace to human health. RA is characterized by recurrent pain and is difficult to resolve, necessitating prolonged medication for control. Yishen Tongbi decoction is a traditional Chinese herbal compound prescribed for treating RA. We have completed a 3-year RCT study that confirmed the clinical efficacy of Yishen Tongbi decoction for RA. Notably, we observed a faster clinical remission rate compared to MTX by week 4 of treatment. In our forthcoming study, we intend to conduct a comprehensive assessment of the efficacy and safety of Yishen Tongbi decoction in the real-world treatment of RA through a prospective study. Methods and analysis: This prospective, multicenter, real-world observational study will be conducted at two designated centers in China from October 2023 to August 2025. The study will include 324 patients with active rheumatoid arthritis. One group will receive Yishen Tongbi decoction combined with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The other group will receive standard treatment. Standard treatment can be further divided into subgroups: csDMARDs, targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), and biologic disease-modifying antirheumatic drugs (bDMARDs). In each group, the number of tender joints, number of swollen joints, pain score, patient global assessment, physician global assessment, disease activity index (DAS28-ESR or DAS28-CRP), clinical disease activity index (cDAI), simplified disease activity index (sDAI) and relevant laboratory data will be compared. Clinical indicators and disease activity of the patients will be assessed at baseline, week 4 and week 12 after the initiation of treatment. The primary outcome will be the American College of Rheumatology 20% improvement criteria (ACR20) attainment rate among patients at week 12 after treatment. Every adverse event will be reported. Ethics and dissemination: This study has been approved by the Ethics Committee of the first affiliated Hospital of Guangzhou University of traditional Chinese Medicine (NO.K-2023-009). The results of the study will be published in national and international peer-reviewed journals and at scientific conferences. The researchers will inform participants and other RA patients of the results through health education. Clinical Trial Registration: https://www.chictr.org.cn/index.html, identifier ChiCTR2300076073.

Xiaoyaosan promotes neurotransmitter transmission and alleviates CUMS-induced depression by regulating the expression of Oct1 and Oct3 in astrocytes of the prefrontal cortex.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyaosan (XYS) is a traditional prescription for the treatment of liver depression and qi stagnation, and pharmacological studies have shown that XYS has great potential to reverse depression. However, anti-depression targets and the mechanism of XYS are still not entirely clear. AIM OF THE STUDY: The present study aims to explore and verify the anti-depression mechanism of XYS. MATERIALS AND METHODS: The antidepressant effect of XYS was assessed in rats with depression induced by chronic unpredictable mild stimulation (CUMS). The levels of 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in different brain regions were measured using ELISA. The expression of organic cation transporters (Octs) were detected by western blot and immunohistochemical techniques. Then, Decynium-22 (D22), an Octs inhibitor, was injected into the prefrontal cortex (PFC) to verify the correlation between Octs and depression-like behavior. Then, the effects of XYS on the behavior, neurotransmitter concentration, and Octs expression in D22-induced rats were examined. Finally, primary astrocytes were used to verify the mechanism of XYS exerting anti-depressant activity by regulating Octs. RESULTS: The result showed that XYS had a significant positive impact on the behavior of depression rats induced by CUMS. XYS also improved the secretion of 5-HT, DA, and NE in the PFC, as well as the promotion of Oct1, Oct2, and Oct3 expression in the PFC. These results suggest that XYS has the potential to alleviate depression by enhancing the secretion of neurotransmitters. This may be related to XYS regulation of Oct's expression. When the expression of Octs was inhibited in the PFC, rats exhibited behavior similar to depression, and XYS was able to reverse this behavior, indicating that Octs play a significant role in the development of depression and XYS may exert its antidepressant effects through the regulation of Octs. Furthermore, the study also found that dopamine uptake decreased after inhibiting the expression of Octs, and XYS-containing serum could reverse the downregulation of Oct1 and Oct3 and promote intracellular dopamine homeostasis in the astrocytes. Overall, XYS may exert antidepressant effects by promoting dopamine uptake to improve neurotransmitter transport by regulating the protein expression of Oct1 and Oct3 in astrocytes. CONCLUSIONS: The antidepressant effect of XYS may be attributed to its ability to regulate the expression of Oct1 and Oct3 in astrocytes of the PFC, thereby promoting neurotransmitter transport.

Effect of urbanization and urban forests on water quality improvement in the Yangtze River Delta: A case study in Hangzhou, China.

In the context of rapid global urbanization, the sustainable development of ecosystems should be considered. Accordingly, the Planetary Boundaries theory posits that reducing the amount of nitrogen and phosphorus pollutants entering bodies of water is necessary as excess levels may harm the aquatic environment and reduce in water quality. Thus, based on the long-term monitoring data of representative urban rivers in the Yangtze River Delta region, we evaluated the nitrogen and phosphorus pollution of water bodies in different urbanization stages and further quantified the effect of urban forests on water quality improvement. The results showed that, with the continuous progression of urbanization, the proportion of impervious surface area increased, along with the levels of nitrogen and phosphorus pollution in water bodies. The critical period of water quality deterioration in urban rivers occurred during the medium urbanization level when the proportion of impervious surface area reached 55-65 %, and the probability of an abrupt increase in total nitrogen (TN) and total phosphorus (TP) concentration exceeded 95 %. However, increasing the area of urban forests during this period reduced TN pollution by 36.64 % and TP pollution by 49.03 %. The results of this study support the expansion of urban forests during the medium urbanization stage to improve water quality. Furthermore, our results provide a reference and theoretical basis for urban forest construction as a key aspect of the sustainable development of the urban ecosystem in the Yangtze River Delta and similar regions around world.

Examining the Efficacy of a Hierarchical Management Model in Enhancing Nursing Service Quality and Patient Satisfaction.

Objective: This study investigated the impact of a hierarchical management model on enhancing the quality of nursing services within the nursing department (ND). Methods: A retrospective comparative cohort study was conducted on outpatients treated at the hospital from January 2021 to December 2022. A total of 68 patients admitted from January 2021 to December 2021 were assigned to the control group, while 75 patients admitted from January 2022 to December 2022 were assigned to the observation group. During the study period, a consistent group of nurses was responsible for outpatient care and underwent hierarchical management beginning in January 2022. We compared nursing quality and patient satisfaction between the two groups and documented adverse events (AEs), which included medical disputes and misdiagnoses. The psychological status of the patients was assessed using the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). Results: In comparison to the control group, the observation group demonstrated significantly higher scores for nursing quality and patient satisfaction (P < .05) and a lower incidence of AEs (P < .05). Following diagnosis and treatment, the observation group exhibited decreased SAS and SDS scores, significantly lower than the control group (P < .05). Conclusions: Implementing a hierarchical management model positively impacts nursing quality within the ND and enhances patient satisfaction. Therefore, it is recommended as an effective approach for improving nursing care quality and patient satisfaction.

Imazethapyr disrupts plant phosphorus homeostasis and acquisition strategies.

The deficiency of essential mineral nutrients caused by xenobiotics often results in plant mortality or an inability to complete its life cycle. Imazethapyr, a widely utilized imidazolinone herbicide, has a long-lasting presence in the soil-plant system and can induce toxicity in non-target plants. However, the effects of imazethapyr on mineral nutrient homeostasis remain poorly comprehended. In this study, Arabidopsis seedlings exposed to concentrations of 4 and 10 µg/L imazethapyr showed noticeable reductions in shoot development and displayed a distinct dark purple color, which is commonly associated with phosphorus (P) deficiency in crops. Additionally, the total P content in both the shoots and roots of Arabidopsis significantly decreased following imazethapyr treatment when compared to the control groups. Through the complementary use of physiological and molecular analyses, we discovered that imazethapyr hinders the abundance and functionality of inorganic phosphorus (Pi) transporters and acid phosphatase. Furthermore, imazethapyr impairs the plant's Pi-deficiency adaptation strategies, such as inhibiting Pi transporter activities and impeding root hair development, which ultimately exacerbate P starvation. These results provide compelling evidence that residues of imazethapyr have the potential to disrupt plant P homeostasis and acquisition strategies. These findings offer valuable insights for risk assessment and highlight the need to reconsider the indiscriminate use of imazethapyr, particularly under specific scenarios such as nutrient deficiency.

Fast Detection of Heavy Metal Content in Fritillaria thunbergii by Laser-Induced Breakdown Spectroscopy with PSO-BP and SSA-BP Analysis.

Fast detection of heavy metals is important to ensure the quality and safety of herbal medicines. In this study, laser-induced breakdown spectroscopy (LIBS) was applied to detect the heavy metal content (Cd, Cu, and Pb) in Fritillaria thunbergii. Quantitative prediction models were established using a back-propagation neural network (BPNN) optimized using the particle swarm optimization (PSO) algorithm and sparrow search algorithm (SSA), called PSO-BP and SSA-BP, respectively. The results revealed that the BPNN models optimized by PSO and SSA had better accuracy than the BPNN model without optimization. The performance evaluation metrics of the PSO-BP and SSA-BP models were similar. However, the SSA-BP model had two advantages: it was faster and had higher prediction accuracy at low concentrations. For the three heavy metals Cd, Cu and Pb, the prediction correlation coefficient (Rp2) values for the SSA-BP model were 0.972, 0.991 and 0.956; the prediction root mean square error (RMSEP) values were 5.553, 7.810 and 12.906 mg/kg; and the prediction relative percent deviation (RPD) values were 6.04, 10.34 and 4.94, respectively. Therefore, LIBS could be considered a constructive tool for the quantification of Cd, Cu and Pb contents in Fritillaria thunbergii.

[Regulation of ischemic stroke by circadian rhythm and intervention by traditional Chinese medicine].

Circadian rhythm is an internal regulatory mechanism formed in organisms in response to the circadian periodicity in the environment, which modulates the pathophysiological events, occurrence and development of diseases, and the response to treatment in mammals. It significantly influences the susceptibility, injury, and recovery of ischemic stroke, and the response to therapy. Accumulating evidence indicates that circadian rhythms not only regulate the important physiological factors of ischemic stroke events, such as blood pressure and coagulation-fibrinolysis system, but also participate in the immuno-inflammatory reaction mediated by glial cells and peripheral immune cells after ischemic injury and the regulation of neurovascular unit(NVU). This article aims to link molecular, cellular, and physiological pathways in circadian biology to the clinical consequences of ischemic stroke and to illustrate the impact of circadian rhythms on ischemic stroke pathogenesis, the regulation of NVU, and the immuno-inflammatory responses. The regulation of circadian rhythm by traditional Chinese medicine is reviewed, and the research progress of traditional Chinese medicine intervention in circadian rhythm is summarized to provide a reasonable and valuable reference for the follow-up traditional Chinese medicine research and molecular mechanism research of circadian rhythm.

Anti-proliferation and anti-migration effects of Yishen Tongbi decoction in experimental rheumatoid arthritis by suppressing SLC3A2/integrin ß3 signaling pathways.

BACKGROUND: Yishen Tongbi (YSTB) decoction is a patented herbal formula that is used in China to treat rheumatoid arthritis (RA); however, the exact mechanism of its anti-synovial hyperplasia efficacy has not been fully elucidated. PURPOSE: Based on our previous proteomics study, we aimed to reveal whether YSTB inhibits the proliferation and migration of RA-FLSs through the SLC3A2/integrin ß3 pathway in vivo and in vitro. STUDY DESIGN: The study design consists of three parts, a comparison of the expression of SLC3A2 and integrin ß3 in synovial tissues of RA and OA patients; an animal experiment to verify the pharmacodynamic effect of YSTB, and in vitro experiment to elucidate the specific mechanism of YSTB. METHODS: The expression of SLC3A2 and integrin ß3 in the synovial tissues of patients with RA and osteoarthritis (OA) patients were detected by immunohistochemistry (IHC). In vitro, firstly, the proliferation and migration abilities of HFLS (human fibroblast-like synoviocytes) and HFLS-RA (human fibroblast-like synoviocytes-RA) cells were compared by EdU staining and wound healing assays, respectively, and the differences in the expression and localization of SLC3A2, integrin ß3, p-FAK and p-Src between HFLS and HFLS-RA cells were detected by IF and WB. In vivo, DBA/1 mice were injected with bovine collagen II to construct a CIA mouse model. Paw swelling, body weight and the arthritis index (AI) were used as basic treatment evaluation indicators for YSTB. Micro-CT and histopathological analyses of the knee and ankle joints were also performed. In addition, the expression of SLC3A2, integrin ß3, p-FAK and p-Src in the synovial tissue of mice was detected by IHC. Subsequently, CCK-8 was used to screen for suitable concentrations of YSTB for use in HFLS-RA cells. EdU staining and transwell migration assays were performed to evaluate the inhibitory effect of YSTB on cell proliferation and migration, and WB was conducted to assess whether YSTB inhibited HFLS-RA migration through downregulation of the SLC3A2/integrin ß3 pathways. RESULTS: IHC showed that the expression of SLC3A2 and integrin ß3 was higher in RA synovial tissues than in OA tissues. In vivo experiments showed that YSTB inhibited synovial hyperplasia, prevented bone destruction, and reduced the expression of SLC3A2, integrin ß3, p-FAK and p-Src. In vitro experiments showed that YSTB inhibited HFLS-RA migration and proliferation by inhibiting the expression of SLC3A2/integrin ß3 and downstream signaling molecules. CONCLUSION: YSTB inhibits the proliferation and migration of synovial fibroblasts in RA by downregulating the SLC3A2/integrin ß3 pathways.

Effectiveness of Yishen Tongbi decoction versus methotrexate in patients with active rheumatoid arthritis: A double-blind, randomized, controlled, non-inferiority trial.

BACKGROUND: Yishen Tongbi decoction (YSTB) which is an herbal formula, has been used for the treatment of rheumatoid arthritis (RA) for more than ten years with a better curative effect. Methotrexate (MTX) is an effective anchoring agent used to treat rheumatoid arthritis. There were, however, no head-to-head comparative randomized controlled trials comparing traditional Chinese medicine (TCM) to MTX, Therefore, we performed this double-blind, double-model, randomized controlled trial of the efficacy and safety of YSTB and MTX in the treatment of active RA for 24 weeks. METHODS: Patients who met the enrollment criteria were randomly selected (1:1) to receive either YSTB therapy (YSTB 150 ml once daily + MTX placebo 7.5-15 mg once weekly) or MTX therapy (MTX 7.5-15 mg once weekly + YSTB placebo 150 ml once daily) in treatment cycles lasting 24 weeks. The percentage of patients who achieve a clinical disease activity index (CDAI) response at week 24 is the primary efficacy outcome. A 10% risk differential non-inferiority margin was previously defined. The Chinese Clinical Trials Registry has recorded this trial (ChiCTR-1,900,024,902, registered on August 3rd 2019, http://www.chictr.org.cn/index.aspx). RESULTS: Out of 118 patients whose eligibility was determined from September 2019 to May 2022, 100 patients (n = 50 for each group) were enrolled in the research overall. The 24-week trial was completed by 82% (40/49) of the YSTB group's patients and 86% (42/49) of the MTX group's patients. In the intention-to-treat analysis, 67.4% (33/49) of patients in the YSTB group met the main outcome of CDAI response criteria at week 24, compared to 57.1% (28/49) in the MTX group. The risk difference was 0.102 (95% CI -0.089 to 0.293), which demonstrated the non-inferiority of YSTB to MTX. After further testing for superiority, the ratio of CDAI responses achieved by the YSTB and MTX groups was not statistically significant (p = 0.298). At the same time, in week 24, secondary outcomes such as the ACR 20/50/70 response, the European Alliance of Associations for Rheumatology good or moderate response, remission rate, simplified disease activity index response, and low disease activity rate all showed similar statistically significant patterns. There was statistically significant attainment of ACR20 (p = 0.008) and EULAR good or moderate response (p = 0.009) in two groups at week 4. The intention-to-treat analysis results and the per-protocol analysis results were in agreement. The incidence of drug-related adverse events was not statistically different between the two groups (p = 0.487). CONCLUSIONS: Previous studies have used TCM as an adjunct to conventional therapy, and few of them have directly compared it with MTX. In order to lessen disease activity in RA patients, this trial demonstrated that YSTB compound monotherapy was non-inferior to MTX monotherapy and had superior efficacy following short-term treatment. This study provided evidence-based medicine in the treatment of RA with compound prescriptions of TCM and contributed to promoting phytomedicine use in RA patients.

High-throughput Treg cell receptor sequencing reveals differential immune repertoires in rheumatoid arthritis with kidney deficiency.

Background: Regulatory T (Treg) cells are important immune cells that are regulated by adaptive immunity in the composition of Treg-cell subsets and T-cell receptors (TCRs). Treg cells are related to most autoimmune diseases, such as rheumatoid arthritis (RA). In traditional Chinese medicine (TCM), RA is typically attributed to kidney deficiency (KD) associated with the immunosenescence that causes immune dysfunction and the impaired function of Treg cells. So far, however, no mechanism related to KD and immune repertoires has been identified in RA. Methods: Flow cytometry and high-throughput Treg-cell receptor sequencing were used to investigate the amount of different Treg-cell subsets and the diversity of TCRs between RA patients and healthy subjects, as well as between KD RA and non-KD RA patients. RT-qPCR was used to validate the high-throughput sequencing results. Results: The data showed that the amount of naïve Treg cells in KD patients was less than in non-KD RA patients (P = 0.004) with no significant differences observed between other subsets. In the TCR of Treg cells, the length of complementarity determining region 3 (CDR3) was low and clonotypes increased in the KD group compared with the non-KD group. The diversity and abundance of Treg TCRs were low, as determined by the Hill number. In addition, several V(D)J combinations, such as T-cell receptor beta variable 7-2 (TRBV7-2), TRBV11-1, TRBV13, TRBV15, and TRBJ2-3, varied significantly between the two groups, indicating that KD causes Treg dysfunction. RT-qPCR shows that FOXP3 expression in peripheral blood Treg is lower in KD than in non-KD. Conclusion: The results demonstrate the close correlation between KD and immune repertoires in RA and provide a new evaluation method for RA in TCM.

Preoperative bowel preparation promotes intestinal functional recovery after esophagectomy.

Background: Patients are prone to intestinal dysfunction after esophagectomy. The value of preoperative bowel preparation before esophagectomy is controversial. There is a lack of evidence as to whether preoperative bowel preparation can help patients improve bowel function and shorten the recovery time of bowel function. Objectives: The objectives of this study were to explore whether preoperative bowel preparation can promote the recovery of intestinal function after esophagectomy. Methods: We analysed 139 patients who underwent elective radical esophagectomy in the Department of Thoracic Surgery at the Second Affiliated Hospital of Xi'an Jiaotong University from May 2016 to December 2018. The enrolled patients were divided into the study group (bowel preparation group) and the control group (no bowel preparation group) of 71 cases and 68 cases. Patients in the study group were given dissolved polyethylene glycol electrolyte powder and a cleansing enema the day before surgery. Patients in the control group were neither given polyethylene glycol electrolyte powder nor cleansing enemas before surgery. The postoperative recovery of the two groups were compared. Results: Postoperative bed rest time, bowel function recovery time and the time of first flatus and defecation after surgery were significantly shorter in patients with bowel preparation than in those without bowel preparation, and the differences were statistically significant. (P=0.038, P<0.001, P<0.001, P<0.001; respectively). Conclusions: Preoperative bowel preparation can promote the recovery of patients with esophageal cancer, especially the recovery of bowel function, which can reduce the pain caused by abdominal distension and improve the quality of life of patients.

Vinegar-baked Radix Bupleuri enhances the liver-targeting effect of rhein on liver injury rats by regulating transporters.

OBJECTIVE: This study aimed to explore whether the liver-targeting enhancing effect of vinegar-baked Radix Bupleuri (VBRB) on rhein was achieved by affecting transporters, metabolism enzymes as well as hepatocyte nuclear factor 1α/4α (HNF1α/HNF4α) in liver injury. METHODS: The effect of VBRB on the efficacy of rhein was performed with the LPS-induced acute liver injury rat model. Aspartate aminotransferase (AST), alanine transaminase (ALT) and superoxide dismutase (SOD) levels were determined and histopathological examination was taken. Drug concentrations in tissues were determined by high performance liquid chromatography (HPLC). The protein expressions of drug transporters, metabolic enzymes and hepatic nuclear factors were determined by Western blotting and ELISA assays. KEY FINDING: VBRB improved the liver protecting effect of rhein, which was consistent with its promoting effect on targeted enrichment of rhein in the liver. VBRB or in combination with rhein inhibited P-glycoprotein (Pgp) and multi-resistance related protein 2 (MRP2), while increased organic anion transporting polypeptide 2 (OATP2), which might be the reason why VBRB promoted liver-targeting effect of rhein. CONCLUSION: VBRB enhances the liver-protecting effect of rhein by down-regulating Pgp, MRP2, and up-regulating OATP2.

A source-sink landscape approach to mitigation of agricultural non-point source pollution: Validation and application.

Optimizing landscape pattern to reduce the risk of non-point source (NPS) pollution is an effective measure to improve river water quality. The "source-sink" landscape theory is a recent research tool for landscape pattern analysis that can effectively integrate landscape type, area, spatial location, and topographic features to depict the spatial heterogeneity of NPS pollution. Based on this theory, we quantitatively analyzed the influence of "source-sink" landscape pattern on the river water quality in one of the most intensive agricultural watersheds in Southeastern China. The results indicated that the proportion of "sink" landscape (68.59%) was greater than that of "source" landscape (31.41%) in the study area. In addition, when elevation and slope increased, the "source" landscape proportion decreased, and the "sink" landscape proportion increased. Nitrogen (N) and phosphorus (P) pollutants in rivers showed significant seasonal and spatial variations. Farmland was the primary source of nitrate nitrogen (NO3--N) and total nitrogen (TN) pollution, whereas residential land was the primary source of ammonium nitrogen (NH4+-N) and total phosphorus (TP) pollution. Intensively cultivated areas and densely inhabited areas degraded water quality despite high proportions of forest land. The four "source-sink" landscape indices (LWLI, LWLI'e, LWLI's, LWLI'd) had significant positive correlations with NO3--N and TN and weak correlations with NH4+-N and TP. The capacity of LWLI to quantify the NPS pollution was greater in agricultural areas than in residential areas. The "source-sink" landscape thresholds resulted in abrupt changes in water quality. When LWLI was ∼0.35, the probability of river water quality degradation increased sharply. The results suggest the importance of optimizing the "source-sink" landscape pattern for mitigating agricultural NPS pollution and provide policy makers with adequate new information on the agroecosystem-environmental interface in highly developed agricultural watersheds.

Integrating pharmacokinetics and network pharmacology to identify and validate targets of Guben Xiaozhen prescription for the treatment of chronic urticaria.

ETHNOPHARMACOLOGICAL RELEVANCE: Guben Xiaozhen prescription (GXP), a prescription of traditional Chinese medicine, has been used to treat skin diseases for a long history and achieved satisfactory therapeutic effects. However, its active ingredients and targets remain to be further elucidated. AIM OF THIS STUDY: Identify activity ingredients of GXP for the treatment of chronic urticaria (CU) and further validate the efficacy and targets of the selected component. MATERIALS AND METHODS: Firstly, the pharmacokinetics of different disassemble groups of GXP was investigated to screen for active ingredients with improved bioavailability. Then, shared targets between active ingredients and CU were performed by network pharmacology. Finally, the ovalbumin (OVA) induced CU model was used to verify the efficacy and targets of the screened active ingredient. RESULTS: Pharmacokinetic results showed that, compared with sub-division groups, the maximum concentration (Cmax) and blood concentration-time curve (AUC0-t) of eight ingredients, including 6-shogaol, 6-gingerol, calycosin, dictamnine, fraxinellone, schizandrin, cimifugin, and sec-o-glucosylhamaudol were increased in the GXP group. Then, 218 CU-related targets and 20 shared targets with six potential active compounds were screened by network pharmacology. Further analysis found that fraxinellone was not reported to be associated with CU in the literature. Therefore, the present study employed an OVA-induced CU model and found that fraxinellone could dose-dependently inhibit the locus coeruleus reaction, mast cell degranulation, and pathological skin damage. Moreover, we further verified the ADRB2 and its downstream target caspase3 predicted by network pharmacology, and fraxinellone inhibited the expression of ADRB2 and caspase3 in high dose group, suggesting that fraxinellone may play an anti-CU role by inhibiting inflammation and cell apoptosis. CONCLUSION: In this study, integrated pharmacokinetics and network pharmacology methods were established to screen out six effective active ingredients in GXP for the treatment of CU. This study provides a new idea for screening active substances in traditional Chinese medicine.

Suppression of NLRP3 Inflammasome by Dihydroarteannuin via the HIF-1α and JAK3/STAT3 Signaling Pathway Contributes to Attenuation of Collagen-Induced Arthritis in Mice.

Dihydroarteannuin (DHA), the primary element of artemisinin extracted from the traditional Chinese herb Artemisia annua L., has been used in malaria treatment for a long time. Recently, many studies have indicated that DHA also exhibits potent anti-rheumatoid arthritis (RA) activity. In this study, collagen-induced arthritis (CIA) in DBA/1J mice and inflammatory model in THP-1 cells were established to evaluate the modulatory effects of DHA on joint destruction and to explore the underlying mechanisms. Our results showed that DHA decreased the serum levels of IL-1ß and IL-6, alleviated paw oedema, and reduced bone destruction in DBA/1J mice with CIA. Further exploration with the inflammatory model in THP-1 cells indicated that DHA reduced the protein expression of hypoxia-inducible factor (HIF)-1α and the phosphorylation in Janus kinase (JAK) 3 and signal transducer and activator of transcription (STAT) 3 protein, which resulted in a decrease in NOD-like receptor protein (NLRP) 3 expression and interleukin (IL)-1ß release. Consequentially, the inflammatory activation in THP-1 cells was inhibited. Therefore, we concluded that DHA efficiently alleviated the inflammation and arthritic symptoms in CIA mice and downregulated inflammation in part by inhibiting NLRP3 expression via the HIF-1α and JAK3/STAT3 signaling pathway. Thus, DHA may be considered as a potential therapeutic agent in RA treatment.

Metabolic disturbance in lettuce (Lactuca sativa) plants triggered by imidacloprid and fenvalerate.

Intensive and indiscriminate use of insecticides in agroecosystems causes phytotoxic disturbances in non-target crops. However, the mechanisms by which plants reprogram cellular metabolites to resist and tolerate such agrochemicals remain unclear. Here, the interaction between lettuce plants with imidacloprid and fenvalerate was investigated by the complementary use of physiological and metabolomic analyses. Neither imidacloprid nor fenvalerate induced overt phytotoxicity in lettuce seedlings. The plant biomass, chlorophyll fluorescence, lipid peroxidation, and membrane integrity were not significantly affected by the selected insecticides. Flavonoid content decreased by 25% in lettuce leaves under fenvalerate exposure, whereas polyphenol and flavonoid contents were not significantly altered by imidacloprid. Although the content of most of the nutrient element in the leaves remained the same following pesticide treatment, iron content decreased by 28.1% under imidacloprid exposure but increased by 22.8% under fenvalerate exposure. Metabolomic analysis revealed that the selected insecticides induced extensive metabolic reprogramming in lettuce roots and shoots. Imidacloprid dramatically increased the metabolism of several amino acids (arginine, cysteine, homoserine, and 4-hydroxyisoleucine), whereas markedly decreased the metabolism of various carbohydrates (glucose, raffinose, maltotetraose, maltopentaose, and stachyose). Fenvalerate did not significantly alter amino acid metabolism but decreased carbohydrate metabolism. Additionally, the relative abundance of most organic acids and polyphenolic compounds decreased significantly after pesticide exposure. These results suggest that plants might program their primary and secondary metabolism to resist and tolerate insecticides. The findings of this study provide important information on how neonicotinoid and pyrethroid insecticides affect the health and physiological state of plants, which are ultimately associated with crop yield and quality.

Identifying the Effect of Ursolic Acid Against Triple-Negative Breast Cancer: Coupling Network Pharmacology With Experiments Verification.

Triple negative breast cancer (TNBC) is a subtype of breast cancer with complex heterogeneity, high invasiveness, and long-term poor prognosis. With the development of molecular pathology and molecular genetics, the gene map of TNBC with distinctive biological characteristics has been outlined more clearly. Natural plant extracts such as paclitaxel, vinblastine, colchicine etc., have occupied an important position in the treatment of hormone-independent breast cancer. Ursolic acid (UA), a triterpenoid acid compound derived from apple, pear, loquat leaves, etc., has been reported to be effective in a variety of cancer treatments, but there are few reports on the treatment of TNBC. This study performed comprehensive bioinformatics analysis and in vitro experiments to identify the effect of UA on TNBC treatment and its potential molecular mechanism. Our results showed that UA could not only reduce the proliferation, migration, and invasion in MDA-MB-231 and MDA-MB-468 cell lines with a dose-dependent manner but also induce cell cycle arrest and apoptosis. Meanwhile, we collected the gene expression data GSE45827 and GSE65194 from GEO for comparison between TNBC and normal cell type and obtained 724 DEGs. Subsequently, PLK1 and CCNB1 related to TNBC were screened as the key targets via topological analysis and molecular docking, and gene set enrichment analysis identified the key pathway as the p53 signaling pathway. In addition, quantitative real-time PCR and western blot verified the key genes were PLK1 and CCNB1. In vivo and in vitro experiments showed that UA could inhibit the growth of TNBC cells, and down-regulate the protein expression levels of PLK1 and CCNB1 by mediating p53 signaling pathway. These findings provide strong evidence for UA intervention in TNBC via multi-target therapy.

Polyethylene glycol-coated ultrasmall superparamagnetic iron oxide nanoparticles-coupled sialyl Lewis X nanotheranostic platform for nasopharyngeal carcinoma imaging and photothermal therapy.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a type of head and neck malignant tumor with a high incidence in specific regional distribution, and its traditional therapies face some challenges. It has become an urgent need to seek new therapeutic strategies without or with low toxicity and side effects. At present, more and more researchers has been attracting attention by nanotheranostic platform. Therefore, our team synthesized the polyethylene glycol-coated ultrasmall superparamagnetic iron oxide nanoparticles-coupled sialyl Lewis X (USPIO-PEG-sLex) nanotheranostic platform with high temperature pyrolysis. RESULTS: The USPIO-PEG-sLex nanoparticles had excellent photothermal conversion property, and the temperature of USPIO-PEG-sLex nanoparticles solution increased with its concentration and power density of near-infrared (NIR) on 808 nm wavelengths. Five USPIO-PEG-sLex nanoparticles with different concentrations of 0 mg/ml, 0.025 mg/ml, 0.05 mg/ml, 0.1 mg/ml and 0.2 mg/ml were prepared. The biological toxicity results showed that the viability of NPC 5-8F cells is related to the concentration of USPIO-PEG-sLex nanoparticles and the culture time (P < 0.001). The results of photothermal therapy (PTT) in vitro indicated that the viability of 5-8F cells decreased significantly with the concentration of USPIO-PEG-sLex nanoparticles increases (P < 0.001), and the viability of NPC 5-8F cells were 91.04% ± 5.20%, 77.83% ± 3.01%, 73.48% ± 5.55%, 59.50% ± 10.98%, 17.11% ± 3.14%, respectively. The USPIO-PEG-sLex nanoparticles could target the tumor area, and reduce the T2* value of tumor tissue. The T2* values of tumor pre- and post-injection were 30.870 ± 5.604 and 18.335 ± 4.351, respectively (P < 0.001). In addition, USPIO-PEG-sLex nanoparticles as a photothermal agent for PTT could effectively inhibit tumor progression. The ratio of volume change between tail vein injection group, control group, nanoparticles without laser irradiation group and blank group after 5 treatments were 3.04 ± 0.57, 5.80 ± 1.06, 8.09 ± 1.96, 7.89 ± 2.20, respectively (P < 0.001). CONCLUSIONS: Our synthesized USPIO-PEG-sLex nanotheranostic platform, and it may be become a new strategy for the treatment of NPC.