[Mechanism of traditional Chinese medicine in treating ulcerative colitis-related colorectal cancer by regulating NF-κB-related signaling pathways: a review].

Ulcerative colitis is a chronic, recurrent, and nonspecific intestinal inflammatory disease, which is difficult to cure and has the risk of deterioration into related tumors. Long-term chronic inflammatory stimulation can increase the risk of cancerization. With the signaling pathway as a key link in the regulation of tumor microenvironments, nuclear factor-kappa B(NF-κB) is an important regulator of intestinal inflammation. It can also be co-regulated as downstream factors of other signaling pathways, such as TLR4, MAPK, STAT, PI3K, and so on. At present, a large number of animal experiments have proved that traditional Chinese medicine(TCM) can reduce inflammation by interfering with NF-κB-related signaling pathways, improve intestinal inflammation, and inhibit the progression of inflammation to tumors. This article reviewed the relationship between NF-κB-related signaling pathways and the intervention mechanism of TCM, so as to provide a reference for the clinical treatment of ulcerative colitis and the optimization of related cancer prevention strategies.

Relationship of dietary intake of food folate and synthetic folic acid intake from fortified foods with all-cause mortality in individuals with chronic kidney disease.

OBJECTIVE: To evaluate the association of the dietary intake of food folate (natural folate) and synthetic folic acid intake from fortified foods with the risk of all-cause mortality and end-stage kidney disease (ESKD) among the chronic kidney disease (CKD) population in regions with folic acid fortification. METHODS: 4028 individuals with established CKD in Chronic Renal Insufficiency Cohort (CRIC) were included. Diet was assessed using a validated diet history questionnaire at the baseline, year 2, and year 4, and nutrient intake, including food folate and folic acid from fortified foods, was estimated using the National Nutrient Database. The outcomes were all-cause mortality and ESKD. The results for all-cause mortality were further validated using the data from National Health and Nutrition Examination Surveys (NHANES). RESULTS: During a median follow-up of 11.1 years, 1155 deaths and 938 ESKD cases occurred. Compared with the first quartile of food folate intake, the third (HR: 0.74; 95% CI: 0.62, 0.90) and fourth (HR: 0.79; 95% CI: 0.63, 0.98) quartiles had a lower risk of all-cause mortality. Nevertheless, there was no significant association of synthetic folic acid intake from fortified foods with all-cause mortality. Similar results were observed for ESKD. Consistently, in NHANES, food folate intake and serum 5-methyltetrahydrofolate, but not folic acid intake, were inversely associated with all-cause mortality, while serum unmetabolized folic acid was positively associated with all-cause mortality in CKD participants. CONCLUSIONS: Higher intake of dietary natural folate, but not synthetic folic acid intake from fortified foods, was associated with lower risks of all-cause mortality and ESKD among CKD participants.

Gut microbiota controls the development of chronic pancreatitis: A critical role of short-chain fatty acids-producing Gram-positive bacteria.

Chronic pancreatitis (CP) is a progressive and irreversible fibroinflammatory disorder, accompanied by pancreatic exocrine insufficiency and dysregulated gut microbiota. Recently, accumulating evidence has supported a correlation between gut dysbiosis and CP development. However, whether gut microbiota dysbiosis contributes to CP pathogenesis remains unclear. Herein, an experimental CP was induced by repeated high-dose caerulein injections. The broad-spectrum antibiotics (ABX) and ABX targeting Gram-positive (G+) or Gram-negative bacteria (G-) were applied to explore the specific roles of these bacteria. Gut dysbiosis was observed in both mice and in CP patients, which was accompanied by a sharply reduced abundance for short-chain fatty acids (SCFAs)-producers, especially G+ bacteria. Broad-spectrum ABX exacerbated the severity of CP, as evidenced by aggravated pancreatic fibrosis and gut dysbiosis, especially the depletion of SCFAs-producing G+ bacteria. Additionally, depletion of SCFAs-producing G+ bacteria rather than G- bacteria intensified CP progression independent of TLR4, which was attenuated by supplementation with exogenous SCFAs. Finally, SCFAs modulated pancreatic fibrosis through inhibition of macrophage infiltration and M2 phenotype switching. The study supports a critical role for SCFAs-producing G+ bacteria in CP. Therefore, modulation of dietary-derived SCFAs or G+ SCFAs-producing bacteria may be considered a novel interventive approach for the management of CP.

Association of unsweetened and sweetened tea consumption with the risk of new-onset chronic kidney disease: Findings from UK Biobank and Coronary Artery Risk Development in Young Adults (CARDIA) study.

Background: The association between tea consumption and chronic kidney disease (CKD) remained inconsistent. We aimed to evaluate the association of tea consumption with new-onset CKD and examine the effects of common additives (milk and sweeteners) and genetic variations in caffeine metabolism on the association. Methods: 176 038 and 3104 participants free of CKD at baseline in the United Kingdom Biobank (UK Biobank) and Coronary Artery Risk Development in Young Adults (CARDIA) study were included, respectively. Dietary information was collected using 24-hour dietary recall questionnaires. The study outcome was new-onset CKD. Results: In the UK Biobank, during a median follow-up of 12.13 years, 3535 (2.01%) participants developed CKD. Compared with tea non-consumers, the risk of new-onset CKD was significantly lower in unsweetened tea consumers (hazard ratio (HR) = 0.84, 95% confidence interval (CI) = 0.76-0.93), but not in sweetened tea consumers (HR = 0.96, 95% CI = 0.85-1.08), regardless of whether milk was added to tea. Accordingly, relative to tea non-consumers, the adjusted HRs (95% CIs) of new-onset CKD for participants who reported drinking unsweetened tea 1.5 or fewer, >1.5 to 2.5, >2.5 to 3.5, >3.5 to 4.5, and >4.5 drinks/d were HR = 0.86, 95% CI = 0.75-0.99; HR = 0.88, 95% CI = 0.78-1.00; HR = 0.83, 95% CI = 0.73-0.94; HR = 0.83, 95% CI = 0.72-0.95; and HR = 0.86, 95% CI = 0.75-0.99. Moreover, the association of unsweetened tea consumption with new-onset CKD was stronger among those with faster genetically predicted caffeine metabolism levels, although the interaction was insignificant (P-value interaction = 0.768). Consistently, in the CARDIA study, compared with tea non-consumers, a significantly lower risk of new-onset CKD was found in unsweetened tea consumers (HR = 0.80, 95% CI = 0.65-0.98) but not in sweetened tea consumers (HR = 0.97, 95% CI = 0.70-1.34). Conclusions: Compared with tea non-consumers, consumption of unsweetened tea, but not sweetened tea, was significantly associated with a lower risk of new-onset CKD, regardless of whether milk was added.

Habitual glucosamine use, APOE genotypes, and risk of incident cause-specific dementia in the older population.

BACKGROUND: The relationship of glucosamine use with incident dementia in the older population remains uncertain. We aimed to evaluate the longitudinal association between habitual glucosamine supplement and the risk of cause-specific dementia and examine the possible effect modifiers on this association. METHODS: The study included 214,945 participants over the age of 60 who had available information on glucosamine use and did not have dementia at baseline in the UK Biobank. The APOE genotypes were determined by a combination variant of rs429358 and rs7412. The primary outcome was incident vascular dementia, incident Alzheimer's disease, and incident frontotemporal dementia, respectively. RESULTS: Over a median follow-up duration of 12 years, 1039, 1774, and 122 participants developed vascular dementia, Alzheimer's disease, and frontotemporal dementia, respectively. Overall, habitual glucosamine use was significantly associated with a lower risk of incident vascular dementia (adjusted HR, 0.82; 95%CI, 0.70-0.96), but not significantly associated with incident Alzheimer's disease (adjusted HR, 1.02; 95%CI, 0.92-1.14) and incident frontotemporal dementia (adjusted HR, 0.95; 95%CI, 0.63-1.43). Moreover, the inverse association between habitual glucosamine use and incident vascular dementia was more pronounced in participants with concomitant supplement of calcium (P-interaction = 0.011), and those without concomitant supplement of zinc (P-interaction = 0.018). However, APOE ε4 dosage and baseline cognitive function did not significantly modify the relationships of glucosamine use with incident vascular dementia or Alzheimer's disease (All P-interactions > 0.05). CONCLUSIONS: Regardless of APOE genotypes and baseline cognitive function, habitual glucosamine use was significantly inversely associated with incident vascular dementia in the older population.

Asperosaponin VI protects alcohol-induced hepatic steatosis and injury via regulating lipid metabolism and ER stress.

BACKGROUND: Asperosaponin VI (AVI) is a natural triterpenoid saponin isolated from Dipsacus asper Wall with documented anti-inflammatory and bone protective effects. Our previous work reported that AVI protects the liver of septic mice from acute inflammatory damage. In this paper, we further explored the protective effect and the potential mechanisms of AVI in alcoholic fatty liver disease (AFLD). METHODS: The Lieber-Decarli model was constructed to evaluate the effect of AVI on AFLD in C57BL/6 J mice. Additional in vitro work was performed to investigate HepG2 cells exposed to alcohol, then analyzed the degree of liver injury by detecting the ALT and AST levels both in the liver and serum. H&E staining and Sirius red staining were used to evaluate the histopathology variations in the liver. Further, observe lipid droplets in the cytoplasm by Oil Red O staining. We detected the expression of inflammatory cytokines with qualitative PCR; ROS, MDA, SOD, and GSH-px levels were analyzed to observe oxidative stress. Finally, exploring the activation of AMPK signaling pathway by real-time PCR and Western blotting. RESULTS: Histological examination of liver tissue combined with serum ALT and AST levels showed a significant protective effect of AVI against alcoholic liver injury in AFLD mice. Compared with the model group, AVI evidently improved antioxidant capacity, reduced inflammatory response and lipid accumulation both in vitro and in vivo. For mechanically, it was found that AVI up-regulated phosphorylation level of AMP-activated protein kinase (AMPK) and inhibited the endoplasmic reticulum stress (ER) pathway in AFLD. CONCLUSION: AVI protects mice from alcohol-induced hepatic steatosis and liver injury through activating AMPK signaling and repress ER stress, suggesting that it might be a potential therapeutic agent for AFLD.

Ethyl Lithospermate Reduces Lipopolysaccharide-Induced Inflammation through Inhibiting NF-κB and STAT3 Pathways in RAW 264.7 Cells and Zebrafish.

OBJECTIVE: To explore the anti-inflammatory effects of ethyl lithospermate in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine-derived macrophages and zebrafish, and its underlying mechanisms. METHODS: 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide (MTT) assays were performed to investigate the toxicity of ethyl lithospermate at different concentrations (12.5-100 µ mol/L) in RAW 264.7 cells. The cells were stimulated with LPS (100 ng/mL) for 12 h to establish an inflammation model in vitro, the production of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor α (TNF-α) were assessed by enzyme linked immunosorbent assay (ELISA). Western blot was used to ascertain the protein expressions of signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa B (NF-κB) p65, phospho-STAT3 (p-STAT3, Tyr705), inhibitor of NF-κB (IκB) α, and phospho-I κB α (p-IκB α, Ser32), and confocal imaging was used to identify the nuclear translocation of NF-κB p65 and p-STAT3 (Tyr705). Additionally, the yolk sacs of zebrafish (3 days post fertilization) were injected with 2 nL LPS (0.5 mg/mL) to induce an inflammation model in vivo. Survival analysis, hematoxylin-eosin (HE) staining, observation of neutrophil migration, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to further study the anti-inflammatory effects of ethyl lithospermate and its probable mechanisms in vivo. RESULTS: The non-toxic concentrations of ethyl lithospermate have been found to range from 12.5 to 100 µ mol/L. Ethyl lithospermate inhibited the release of IL-6 and TNF-α(P<0.05 or P<0.01), decreased IκBα degradation and phosphorylation (P<0.05) as well as the nuclear translocation of NF-κB p65 and p-STAT3 (Tyr705) in LPS-induced RAW 264.7 cells (P<0.01). Ethyl lithospermate also decreased inflammatory cells infiltration and neutrophil migration while increasing the survival rate of LPS-stimulated zebrafish (P<0.05 or P<0.01). In addition, ethyl lithospermate also inhibited the mRNA expression levels of of IL-6, TNF-α, IκBα, STAT3, and NF-κB in LPS-stimulated zebrafish (P<0.01). CONCLUSION: Ethyl lithospermate exerts anti-Inflammatory effected by inhibiting the NF-κB and STAT3 signal pathways in RAW 264.7 macrophages and zebrafish.

Tea Consumption and New-Onset Acute Kidney Injury: The Effects of Milk or Sweeteners Addition and Caffeine/Coffee.

Aims: To explore the relationship between tea consumption and the risk of incident acute kidney injury (AKI) and examine the effects of coffee consumption, genetic variation in caffeine metabolism, and the use of tea additives (milk and sweeteners) on this association. Methods: Using data from the UK Biobank, 498,621 participants who were free of AKI and had information on tea intake were included. Black tea is the main type consumed in this population. Dietary information was collected from standardized and validated Food-Frequency Questionnaire (FFQ). Outcome was incident AKI, determined via primary care data, hospital inpatient data, death register records, or self-reported data at follow-up visits. Results: After a median follow-up period of 12.0 years, 21,202 participants occurred AKI. Overall, there was a reversed J-shaped relation between tea consumption and incident AKI, with an inflection point at 3.5 cup/d (p for nonlinearity < 0.001). The relation was similar among participants with different genetically predicted caffeine metabolism (p-interaction = 0.684), while a more obvious positive association was found between heavy tea consumption and AKI when more coffee was consumed (p-interaction < 0.001). Meanwhile, there was a reversed J-shaped relationship for drinking tea with neither milk nor sweeteners, and a L-shaped association for drinking tea with milk (with or without sweeteners) with incident AKI. However, no significant association was found between drinking tea with sweeteners only and incident AKI. Conclusions: There was a reversed J-shaped relation between tea consumption and incident AKI, suggesting that light to moderate tea consumption, especially adding milk, can be part of a healthy diet.

Salvianolic acids from Salvia miltiorrhiza Bunge and their anti-inflammatory effects through the activation of α7nAchR signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiovascular disease (CVD) is a serious disease with a high incidence rate and mortality. Inflammation is closely related to the occurrence of CVDs. As an essential medicine of promoting blood circulation and removing blood stasis in China, Salvia miltiorrhiza Bunge (Danshen) is widely used to treat CVDs due to its anti-inflammatory and cardiovascular protective effects. Salvianolic acids are the most abundant component in the water extract of S. miltiorrhiza, which has a significant effect on the treatment of CVDs. However, due to the complex composition of salvianolic acids, the active molecules and their underlying mechanisms have not been fully explored. AIM OF THIS STUDY: The present study aims to isolate and identify salvianolic acids from Danshen with anti-inflammatory activity and explore the potential mechanisms of isolates. METHODS: The structures of isolated salvianolic acids were elucidated by UV, IR, NMR, MS and electronic circular dichroism (ECD) calculations. Then anti-inflammatory activities of isolates were screened out by the zebrafish inflammation models. The most active compound was further used to explore the anti-inflammatory mechanisms on LPS-stimulated RAW 264.7 cells. The key inflammatory cytokines IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). The protein expression levels of STAT3, p-STAT3 (Tyr705), NF-κB p65, IκBα, p-IκBα (Ser32) and α7nAchR were determined by Western blotting. The nuclear translocation of p-STAT3 (Tyr705) and NF-κB p65 was evaluated by immunofluorescence assays. Finally, the in vivo anti-inflammatory mechanisms were investigated by observation of neutrophil migration, H&E staining, survival analysis and quantitative PCR (Q-PCR) in LPS-microinjected zebrafish. RESULTS: Two new and four known compounds were isolated from Danshen. Among them, isosalvianolic acid A-1 (C1) and ethyl lithospermate (C5) inhibited neutrophil migrations in three zebrafish inflammation models and C1 with the best activities decreased the secretion of IL-6 and TNF-α and inhibited the expression level of p-IκBα (Ser32) in LPS stimulated RAW 264.7 cells. In addition, C1 also reduced the nuclear translocation of NF-κB p65 and p-STAT3 (Tyr705). Moreover, C1 significantly upregulated the protein expression of α7nAchR, and the knockdown of α7nAchR counteracted the effects of C1 on the production of IL-6 and TNF-α and the expression levels of p-STAT3 (Tyr705), NF-κB p65 and p-IκBα (Ser32). In vivo experiments, C1 decreased the migration and infiltration of inflammatory cells, increased the survival ratio and inhibited the mRNA level of IL-6, TNF-α, STAT3, NF-κB and IκBα in LPS-microinjected zebrafish. CONCLUSION: Two new and four known compounds were isolated from Danshen. Among them, C1 exerted anti-inflammatory activities by activating α7nAchR signaling and subsequently inhibiting STAT3 and NF-κB pathways. This study provided evidence for the clinical application of Danshen and contributed to the development of C1 as a novel in the treatment of cardiovascular disease.

Oxidative stress: Roles in skeletal muscle atrophy.

Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.

Water-solubility croconic acid-bisindole dye with morpholine ring for tumor NIRF/PA imaging and photothermal therapy activated by lysosome pH-response.

A novel croconic acid-bisindole dye CR-630 with a morpholine ring showed good water-solubility and obvious lysosome-targeting. The protonation of the nitrogen atom in the indole and lysosome-targeting of morpholine ring let it exhibit stronger pH-responsive NIR/PA imaging and photothermal effect in the lysosome acidic microenvironment (pH 4.0-5.5) than in the tumor acidic microenvironment. In the animal study, compound CR-630 could NIRF/PA image in the tumor tissues in 1.5-2.0 h, effectively inhibit the growth of the tumor, and even ablate the tumor at the drug dose of 1 mg/kg. It also demonstrated good biosafety. This study gives a new idea to develop water-solubility organic dyes with lysosome targeting, stronger pH-responsive NIRF/PA imaging and PTT for breast cancer.

Associations between Serum 25-hydroxyvitamin D, Sun Exposure Time, Dietary Vitamin D Intake, and New-Onset Acute Kidney Injury among 413,169 UK Adults.

BACKGROUND: The prospective associations of serum 25(OH)D, sun exposure time, and dietary vitamin D with risk of acute kidney injury (AKI) are unclear. OBJECTIVES: We aimed to evaluate the relations of serum 25(OH)D, sun exposure time, and dietary vitamin D intake with new-onset AKI and examine whether genetic susceptibility modified such associations. METHODS: A total of 413,169 participants (mean age was 56.4 y, 47.2% were male) from UK Biobank without prior AKI were included. Sun exposure time was expressed as time spent outdoors. Genetic risk scores were calculated by 263 single nucleotide polymorphisms, which showed significant associations with the estimated glomerular filtration rate. The primary outcome was new-onset AKI. Cox proportional hazards models were used to estimate the HRs and (95% CIs). RESULTS: During a median follow-up duration of 12 y, 16,938 (4.1%) participates developed new-onset AKI. Compared with those with serum 25(OH)D <25 nmol/L, significantly lower risks of new-onset AKI were found between participants with 25(OH)D 25 to <50 nmol/L (adjusted HR: 0.76; 95% CI: 0.73, 0.80), and ≥50 nmol/L (adjusted HR: 0.69; 95% CI: 0.65, 0.72). Moreover, in summer, participants who spent ≥4 h outdoors per day (tertile 3) had a significantly lower risk of new-onset AKI (adjusted HR: 0.90; 95% CI: 0.86, 0.95) than those who spent <2 h outdoors per day (tertile 1). Similar results were found for time spent outdoors in winter. In addition, those in quintile 5 of dietary vitamin D intake showed a lower risk of new-onset AKI (≥4.2 µg/d, adjusted HR: 0.90; 95% CI: 0.82, 0.98) than those in quintile 1 (<1.0 µg/d). Genetic risks of kidney diseases did not significantly modify all the 3 above associations (all P-interactions >0.05). CONCLUSIONS: Serum 25(OH)D concentrations, time spent outdoors, and dietary vitamin D intake were all inversely associated with new-onset AKI, independent of genetic risks for kidney diseases.

Antibiotic-impregnated calcium sulfate for the treatment of pediatric hematogenous osteomyelitis.

BACKGROUND: Antibiotic-impregnated calcium sulfate has excellent curative efficacy in chronic osteomyelitis. However, its curative efficacy in pediatric hematogenous osteomyelitis has not been sufficiently studied. The purpose of this study was to evaluate the curative effects of antibiotic-impregnated calcium sulfate in the treatment of pediatric hematogenous osteomyelitis. METHODS: Overall, twenty-one pediatric patients with hematogenous osteomyelitis treated at our hospital between 2013 and 2018 were included for assessment. The clinical history, clinical manifestation, infection recurrence rate, sinus leakage, incision leakage, pathological fractures, bone growth and surgical procedures were analyzed. RESULTS: The infection recurrence rate was 0% (0/21) at a minimum of 31 months (range 31 to 91 months) of follow-up. Postoperative incision leakage was found in one pediatric patient. Osteolysis was found in one pediatric patient. Acceleration of bone growth occurred in one pediatric patient. Retardation of bone growth occurred in one pediatric patient. Genu valgus deformity occurred in one pediatric patient. CONCLUSIONS: Although noninfectious complications occurred, the curative effect of antibiotic-impregnated calcium sulfate in pediatric hematogenous osteomyelitis was satisfactory.

Associations of habitual glucosamine supplementation with incident gout: a large population based cohort study.

OBJECTIVES: The association between habitual glucosamine use and incident gout has not been examined in previous studies. We aimed to evaluate the association of habitual use of glucosamine with the risk of gout in general population. METHODS: A total of 436,594 participants (55.4% female) without prior gout at baseline who completed a questionnaire on supplementation use, which included glucosamine, in the UK Biobank were enrolled. Incident gout was recorded from self-report, death register, primary care, and hospital admission data. RESULTS: At baseline, 53,433 (22.1%) females and 30,685 (15.8%) males reported habitual glucosamine use. During a median follow-up period of 12.1 years, 1718 (0.7%) females and 5685 (2.9%) males developed gout. After multivariable adjustment for major risk factors, glucosamine use was associated with a significantly lower risk of incident gout in females (hazard ratio [HR], 0.81, 95% confidence interval [CI], 0.71-0.92), but not in males (HR, 1.05, 95% CI, 0.97-1.13), compared with non-use (P-interaction < 0.001). Among females, the inverse association between glucosamine use and gout was stronger in participants with diuretics use (HR, 0.64, 95% CI, 0.50-0.81) than those without diuretics use (HR, 0.89, 95% CI, 0.77-1.03) (P-interaction = 0.015). Moreover, gout genetic risk scores did not significantly modify the association between glucosamine use and the risk of incident gout in males (P-interaction = 0.548) or females (P-interaction = 0.183). CONCLUSIONS: Habitual glucosamine use to relieve osteoarthritis pain was related to lower risk of gout in females, but not in males.

Mechanistic insights on cytotoxicity of KOLR, Cinnamomum pauciflorum Nees leaf derived active ingredient, by targeting signaling complexes of phosphodiesterase 3B and rap guanine nucleotide exchange factor 3.

Protein signaling complexes play important roles in prevention of several cancer types and can be used for development of targeted therapy. The roles of signaling complexes of phosphodiesterase 3B (PDE3B) and Rap guanine nucleotide exchange factor 3 (RAPGEF3), which are two important enzymes of cyclic adenosine monophosphate (cAMP) metabolism, in cancer have not been fully explored. In the current study, a natural product Kaempferol-3-O-(3'',4''-di-E-p-coumaroyl)-α-L-rhamnopyranoside designated as KOLR was extracted from Cinnamomum pauciflorum Nees leaves. KOLR exhibited higher cytotoxic effects against BxCP-3 pancreatic cancer cell line. In BxPC-3 cells, the KOLR could enhance the formation of RAPGEF 3/ PDE3B protein complex to inhibit the activation of Rap-1 and PI3K-AKT pathway, thereby promoting cell apoptosis and inhibiting cell metastasis. Mutation of RAPGEF3 G557A or low expression of PDE3B inactivated the binding action of KOLR resulting in KOLR resistance. The findings of this study show that PDE3B/RAPGEF3 complex is a potential therapeutic cancer target.

Asperosaponin VI protects mice from sepsis by regulating Hippo and Rho signaling pathway.

OBJECTIVE: To explore the novel protective effect of Asperosaponin VI (AVI) on sepsis and its potential mechanism. METHODS: In in vitro experiments, bone marrow mononuclear cells and THP-1-derived cells were used to evaluate the viability of AVI treatment. Besides, the quantitative real-time PCR and Western blot were adopted to explore the protective effect of AVI on LPS-induced inflammation. For in vivo work, the effect of AVI on mice was evaluated by using both CLP-induced and the LPS-induced sepsis mice model. The fluctuation of anal temperature and the behavior of mice were recorded after surgery. Further, the content of bacteria in peritoneal lavage fluid was detected, as well as the levels of ALT, AST, LD and LDH in serum with ELISA. H&E staining and real-time PCR were used to evaluate the histopathology of liver, spleen and lung. Finally, relevant signaling pathways were detected by Western blot, real-time PCR and immunohistochemistry. RESULTS: AVI inhibited the expression of inflammatory factors in both CLP-induced and LPS-induced sepsis mice models, and reduced the number of bacteria in abdominal lavage fluid. The preventive treatment with AVI alleviated sepsis-induced organ injuries, reduced inflammatory responses, which was through inhibiting Hippo and Rho signaling pathway. CONCLUSIONS: This study indicated that AVI effectively protected mice from sepsis by down-regulating the activation of Hippo signaling and Rho family, and reducing inflammation and organ damage. However, conventional treatment was using antibiotics, and its mechanism was different with AVI.

(Micro) nanoplastics promote the risk of antibiotic resistance gene propagation in biological phosphorus removal system.

Microplastics (MPs), nanoplastics (NPs) and antibiotic resistance genes (ARGs), as emerging pollutants, have been frequently detected in wastewater treatment plants. However, the behavior of phosphorus and ARGs under MP and NP (MP/NP) pressure in biological phosphorus removal (BPR) system is still unknown. This study investigated the effects of MP/NPs on phosphorus removal and ARGs propagation in BPR system. Results showed that MP/NPs had no influence on phosphorus removal, but significantly promoted the amplification of tetracycline resistance genes (TRGs). Moreover, the TRG abundance were more facilitated by MPs than NPs, and the TRGs of efflux pump and enzymatic modification mechanism were mainly enriched. Meanwhile, MP/NPs increased the transmission risk of multiple resistance genes and mobile gene elements (MGEs). Microbial communities demonstrated the main polyphosphate accumulating organisms shifted from Acinetobacter to unclassified_Gammaproteobacteria, which explained why phosphorus removal efficiency was unaffected with MP/NP addition. Correlation analysis revealed there was no significant correlation between ARGs and MGEs (intI1 and intI2), but the abundances of potential hosts of ARGs were significantly increased with MP/NP addition, implying microbial community structure changes rather than gene horizontal transfer was the main factor promoting ARG propagation under MP/NP pressure.

Relationship of several serum folate forms with kidney function and albuminuria: cross-sectional data from the National Health and Nutrition Examination Surveys (NHANES) 2011-2018.

We aim to examine the relation of several folate forms (5-methyltetrahydrofolate (5-mTHF), unmetabolised folic acid (UMFA) and MeFox) with kidney function and albuminuria, which remained uncertain. The cross-sectional study was conducted in 18 757 participants from National Health and Nutrition Examination Survey 2011-2018. The kidney outcomes were reduced estimated glomerular filtration rate (eGFR) (<60 ml/min/1·73 m2), microalbuminuria (albumin:creatinine ratio (ACR) of 30-299 mg/g) and macroalbuminuria (ACR ≥ 300 mg/g). Overall, there were significant inverse associations between serum 5-mTHF and kidney outcomes with significant lower prevalence of reduced eGFR (OR, 0·71; 95 % CI: 0·57, 0·87) and macroalbuminuria (OR, 0·65; 95 % CI: 0·46, 0·91) in participants in quartiles 3-4 (v. quartiles 1-2; both Pfor trend across quartiles <0·05). In contrast, there were significant positive relationship between serum UMFA and kidney outcomes with significant higher prevalence of reduced eGFR in participants in quartiles 2-4 (v. quartile 1; OR, 2·12; 95 % CI: 1·45, 3·12; Pfor trend <0·001) and higher prevalence of macroalbuminuria in participants in quartile 4 (v. quartiles 1-3; OR, 1·46; 95 % CI: 1·06, 2·01; Pfor trend <0·001). However, there was no significant associations of 5-mTHF and UMFA with microalbuminuria. In addition, there were significant positive relationships of serum MeFox with reduced eGFR, microalbuminuria and macroalbuminuria (all Pfor trend <0·01). In conclusion, higher 5-mTHF level, along with lower UMFA and MeFox level, was associated with lower prevalence of kidney outcomes, which may help counsel future clinical trials and nutritional guidelines regarding the folate supplement.

Chinese Herbal Medicine Adjusting Brain Microenvironment via Mediating Central Nervous System Lymphatic Drainage in Alzheimer's Disease.

Due to its complex pathogenesis and lack of effective therapeutic methods, Alzheimer's disease (AD) has become a severe public health problem worldwide. Recent studies have discovered the function of central nervous system lymphatic drainage, which provides a new strategy for the treatment of AD. Chinese herbal medicine (CHM) has been considered as a cure for AD for hundreds of years in China, and its effect on scavenging ß-amyloid protein in the brain of AD patients has been confirmed. In this review, the mechanism of central nervous system lymphatic drainage and the regulatory functions of CHM on correlation factors were briefly summarized. The advances in our understanding regarding the treatment of AD via regulating the central lymphatic system with CHM will promote the clinical application of CHM in AD patients and the discovery of new therapeutic drugs.

Habitual Fish Oil Supplementation and Incident Chronic Kidney Disease in the UK Biobank.

BACKGROUND: To explore the relation of habitual fish oil use with the risk of chronic kidney diseases (CKD). METHODS: 408,023 participants (54.2% female) without prior CKD and with completed information regarding their consumption of major food groups and fish oil in the UK Biobank were enrolled. Fish oil use and dietary intakes were assessed by touch screen questionnaire and food frequency questionnaire, respectively. Incident CKD was recorded from hospital inpatient records. RESULTS: At baseline, 128,843 (31.6%) participants reported taking fish oil supplements. During a median follow-up period of 12.0 years, a total of 10,782 (2.6%) participants developed CKD. With adjustments for important confounders, habitual fish oil use was associated with a significantly lower hazard of incident CKD (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.87-0.95), compared with non-use. Consistently, participants reporting ≥2 servings/week of oily fish (HR, 0.86; 95% CI, 0.79-0.94) and nonoily fish (HR, 0.86; 95% CI, 0.77-0.97) consumption had a lower hazard of incident CKD compared to those reporting no consumption ever. Additionally, among the 97,914 participants with data on plasma fatty acid, there were significant inverse relationships of plasma omega-3 polyunsaturated fatty acid (PUFA) (per SD increment, HR, 0.89, 95% CI, 0.84-0.94) and eicosatetraenoic acid (per SD increment, HR, 0.91, 95% CI, 0.87-0.96) with incident CKD. CONCLUSIONS: Habitual fish oil use was associated with a lower hazard of CKD, which was further confirmed by the consistent inverse relations between fish consumption and circulating omega-3 PUFA concentration with incident CKD.